Protoporphyrinogen oxidase inhibitors

ABSTRACT

The present invention relates to protoporphyrinogen oxidase inhibitors of the general formula (I)where the variables are defined herein. The invention features processes and intermediates for preparing the benzoxazinones of formula (I), compositions comprising them, and their use as herbicides—i.e. for controlling harmful plants. The invention also features methods for controlling unwanted vegetation comprising allowing an herbicidal effective amount of at least one benzoxazinone of formula (I) to act on plants, their seed, and/or their habitat.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 63/244,586, filed Sep. 15, 2021, U.S. Provisional Patent ApplicationNo. 63/299,855, filed Jan. 14, 2022, and U.S. Provisional PatentApplication No. 63/400,365, filed Aug. 23, 2022, each of which isincorporated herein by reference in its entirety.

FIELD

The present invention relates to protoporphyrinogen IX oxidase (PPO)inhibitors useful as herbicides. In particular, the present inventionrelates to certain benzoxazinone compounds, including for example5-tetrafluorophenyl benzoxazinone and 6-pentafluorophenyl benzoxazinone;compositions comprising such compounds; processes for making suchcompounds and compositions; and methods for using such compounds forcrop protection and to control unwanted vegetation.

BACKGROUND

Herbicides that inhibit protoporphyrinogen oxidase (hereinafter referredto as Protox or PPO; EC:1.3.3.4), a key enzyme in the biosynthesis ofprotoporphyrin IX, have been used for selective weed control since the1960s. PPO catalyzes the last common step in chlorophyll and hemebiosynthesis, which is the oxidation of protoporphyrinogen IX toprotoporphyrin IX [Matringe M. et al., Protoporphyrinogen oxidase as amolecular target for diphenyl ether herbicides, Biochemistry Journal(1989) 260: 231-235]. Application of PPO-inhibiting herbicides resultsin the accumulation of protoporphyrinogen IX in the chloroplast andmitochondria, which is believed to leak into the cytosol where it isoxidized by a peroxidase. When exposed to light, protoporphyrin IXcauses formation of singlet oxygen in the cytosol and the formation ofother reactive oxygen species, which can cause lipid peroxidation andmembrane disruption leading to rapid cell death [Lee H. J. et al.,Cellular localization of protoporphyrinogen-oxidizing activities ofetiolated barley leaves, Plant Physiology (1993) 102: 881].

To date, thousands of PPO inhibitors have been reported in theliterature, with about 30 currently used as herbicides to decimate weedsin fields [Hao, G. F., et al., Protoporphyrinogen oxidase inhibitor: anideal target for herbicide discovery, Chimia (2011) 65, 961-969].PPO-inhibiting herbicides include many different structural classes ofmolecules, including diphenyl ethers (e.g. lactofen, acifluorfen,acifluorfen methyl ester, or oxyfluorfen); oxadiazoles (e.g. oxadiazon);cyclic imides [e.g. S-23142,N-(4-chloro-2-fluoro-5-propargyloxyphenyl)-3,4,5,6-tetrahydrophthalimide,chlorophthalim, N-(4-chlorophenyl)-3,4,5,6-tetrahydrophthalimide)];phenyl pyrazoles (e.g. TNPP-ethyl, ethyl2-[1-(2,3,4-trichlorophenyl)-4-nitropyrazolyl-5-oxy]propionate, M&B39279); pyridine derivatives (e.g. LS 82-556); and phenopylate and itsO-phenylpyrrolidino- and piperidinocarbamate analogs (Krämer W., ed.,Modern Crop Protection Compounds, 2^(nd) Ed., Vol 1: Herbicides, (2012)Wiley-VCH, Weinheim, Germany). Many of these compounds competitivelyinhibit the normal reaction catalyzed by the enzyme, apparently actingas substrate analogs.

The herbicidal properties of these known compounds towards harmfulplants, however, are not always entirely satisfactory. Herbicideresistant weeds present a serious problem for efficient weed controlbecause such resistant weeds are increasingly widespread and thus weedcontrol by the application of herbicides is no longer effective, causinga huge problem to farmers. Resistance to PPO herbicides has been slow toevolve (about four decades from first commercialization), and to datehas been confirmed in 13 weed species [Heap I, The International Surveyof Herbicide Resistant Weeds. Available online:http://www.weedscience.org/ (October 2019)]. The first weed to evolveresistance to PPO herbicides was waterhemp (Amaranthus tuberculatus) in2001 [Shoup D. E., et al., Common waterhemp (Amaranthus rudis)resistance to protoporphyrinogen oxidase-inhibiting herbicides Weed Sci.(2003) 51:145-150]. Resistance to PPO herbicides in weedy species hasbeen attributed to target-site mutation in the PPX2 gene. For example, aunique target-site amino acid deletion (Gly₂₁₀) and Arg₉₈Leusubstitution confer PPO resistance in waterhemp [Patzoldt W. L., et al.,A codon deletion confers resistance to herbicides inhibitingprotoporphyrinogen oxidase. Proc. Natl. Acad. Sci. USA (2006)103:12329-12334] and common ragweed [Rousonelos, et al.,Characterization of a common ragweed (Ambrosia artemisiifolia)population resistant to ALS- and PPO-inhibiting herbicides, Weed Sci.(2012) 60:335-344], respectively.

Thus, there is a need for novel methods to effectively control weeds,including herbicide resistant weeds and in particular PPO resistantweeds, which at the same time is tolerated by the useful plants (crops)in question.

BRIEF SUMMARY

In some aspects, provided herein are novel PPO inhibitors that have highherbicidal activity, even at low application rates. In some embodiments,improved leaf and root penetration, improved translocation, improvedspectrum, and selectivity are achieved by the benzoxazinones of theinvention, defined below, and by their agriculturally suitable salts andformulations.

Accordingly, in one aspect, provided are benzoxazinones having formulaI:

or a salt thereof, wherein Ring A and R¹-R⁸ are as defined herein. Insome embodiments, Ring A contains at least 4 F atom substituents.

In certain embodiments, provided are benzoxazinones having formula II:

or a salt thereof, wherein R¹-R⁴ as are defined herein.

In certain embodiments, provided are benzoxazinones having formula III:

or a salt thereof, wherein R¹-R⁴ as are defined herein.

In certain embodiments, provided are benzoxazinones having formula IV:

or a salt thereof, wherein R¹-R⁴ as are defined herein.

In other aspects, provided is also an agricultural composition(including, in some variations, herbicidal compositions) that includes acompound of formulas I, II, III, or IV, or a salt thereof, in aherbicidally effective amount and at least one component selected fromthe group consisting of surfactants, solid diluents and liquid diluents(e.g., formulations). In some variations, the salt is an agriculturallysuitable salt. In some embodiments, the composition optionally furtherincludes at least one additional active ingredient. In one variation,the additional active ingredient may be an herbicide and/or herbicidesafener.

In yet another aspect, provided are also processes for making theabove-identified compounds, salts, and compositions.

In certain aspects, provided are compounds that are intermediates formaking one or more compounds of the invention, including one or morecompounds of Table 1, or a salt thereof.

In yet other aspects, provided are also methods for controlling thegrowth of undesired vegetation comprising contacting the vegetation orits environment with a herbicidally effective amount of a compound ofthe invention, its salt, or a composition that includes a compound ofthe invention as described herein.

BRIEF DESCRIPTION OF THE FIGURES

The present application can be understood by reference to the followingdescription taken in conjunction with the accompanying figures.

FIGS. 1A and 1B show percent growth inhibition, necrosis at application,xylem, and phloem mobility for compounds of the invention vs. knowncompounds. In FIG. 1A, for each compound, 2 six-plant trays arerepresented. Plants on the left side of the tray were treated withpenetrant (COC) and on the right side were treated without COC. In FIG.1B, the effect of 3×2 μL droplets without penetrant on the adaxialsurface of emerged Setaria Italica leaf for Compound 2, compound 920-4,and compound 920-6.

FIG. 2A is a photograph showing Compound 2 (60 g ai/ha) PPO dG210 mutantTall Waterhemp (Amaranthus tuberculatus) residual control. FIG. 2B is aphotograph showing Flumioxazin (70 g ai/ha) PPO dG210 resistant TallWaterhemp (Amaranthus tuberculatus) residual control.

DETAILED DESCRIPTION

Benzoxazinone Compounds

In one aspect, provided are benzoxazinones having formula I:

or a suitable salt thereof, wherein:

-   -   R¹ is H or alkyl optionally substituted with R^(1a), phenyl, or        benzyl, wherein each of said alkyl, phenyl or benzyl is        optionally substituted with up to 3 halo atoms, an OH group, or        an O-alkyl group;        -   R^(1a) is

-   -   -   -   each R^(1b) is, independently, H, alkyl, or cyclopropyl;

    -   each of R² and R³ is, independently, H, Cl, F, alkyl, or R² and        R³ together with the intervening carbon is cyclopropyl;

    -   R⁴ is H or F;

    -   R⁵ is H or F;

    -   each of R⁶ and R⁷ is, independently, halo, H, alkyl, alkenyl,        OH, O-alkyl, O-cyclopropyl, OCH₂CCH, NHCH₂Ph, N(R^(x))₂, or        S-(alkyl),        -   wherein the alkyl is optionally substituted with at least            one —OH;

    -   R⁸ is H or halo;

    -   each R^(x) is, independently, H, alkyl, or C(O)alkyl; and

    -   wherein Ring A contains at least 4 halo substituents.

In some variations of the foregoing:

-   -   R¹ is H or C₁₋₄alkyl optionally substituted with Ria, phenyl, or        benzyl, wherein each of said alkyl, phenyl or benzyl is        optionally substituted with up to 3 F atoms, an OH group, or an        OC₁₋₄alkyl group;        -   R^(1a) is

-   -   -   -   each R^(1b) is, independently, H, C₁₋₄alkyl, or                cyclopropyl;

    -   each of R² and R³ is, independently, H, Cl, F, CH₃, or R² and R³        together with the intervening carbon is cyclopropyl;

    -   R⁴ is H, Cl or F;

    -   R⁵ is H or F;

    -   each of R⁶ and R⁷ is, independently, F, H, C₁₋₂alkyl, alkenyl,        OH, OC₁₋₂alkyl, O-cyclopropyl, OCH₂CCH, NHCH₂Ph, N(R^(x))₂, or        SCH₃,        -   wherein the C₁₋₂alkyl is optionally substituted with at            least one —OH;

    -   R_(x) is H or F;

    -   each R^(x) is, independently, H, CH₃, or C(O)CH₃; and

    -   wherein Ring A contains at least 4 F atom substituents.

In one embodiment, each of R², R³, and R⁴ of a compound of formula I isF. In another embodiment, each of R², R³, and R⁴ of a compound offormula I is F, and R¹ is CH₂CCH (i.e., C₁₋₄alkyl substituted withR^(1a), wherein R^(1a) is

and R^(1b) is H). In some variations, each of R² and R³ is,independently, H, F, CH₃, or R² and R³ together with the interveningcarbon is cyclopropyl.

In some variations, each of R⁴ and R⁵ is, independently, H or F.

In another further embodiment, each of R² and R³ in a compound offormula I is H and R⁴ is F.

In one embodiment, each of R² and R³ in a compound of formula I is F,and each of R⁴ and R⁵ is H.

In certain variations, each of R⁶ and R⁷ is, independently, F, H,C₁₋₂alkyl optionally substituted with OH, alkenyl, OH, OC₁₋₂alkyl,O-cyclopropyl, OCH₂CCH, NHCH₂Ph, N(R^(x))₂, or SCH₃. In one variation,each of R⁶ and R⁷ is, independently, F, H, C₁₋₂alkyl, alkenyl, OH,OC₁₋₂alkyl, N(R^(x))₂, N(R^(x))C(O)CH₃, or SCH₃.

In some variations, each R^(x) is, independently, H or CH₃.

In another embodiment, the invention features benzoxazinones havingformula II.

or a salt thereof.

In a further embodiment, each of R², R³, and R⁴ in a compound of formulaII is F. In another embodiment, each of R², R³, and R⁴ of a compound offormula II is F, and R¹ is CH₂CCH (i.e., C₁₋₄alkyl substituted withR^(1a), wherein R_(1a) is

and R^(1b) is H).

In another further embodiment, each of R² and R³ in a compound offormula II is H and R⁴ is F.

In another embodiment, the invention features benzoxazinones havingformula II:

or a salt thereof.

In a further embodiment, each of R², R³, and R⁴ of a compound of formulaIII is F. In another embodiment, each of R², R³, and R⁴ of a compound offormula III is F, and R¹ is CH₂CCH (i.e., C₁₋₄alkyl substituted withR^(1a), wherein R^(1a) is

and R^(1b) is H).

In another further embodiment, each of R² and R³ in a compound offormula III is H and R⁴ is F.

In another embodiment, the invention features benzoxazinones havingformula IV:

or a salt thereof.

In a further embodiment, each of R², R³, and R⁴ in a compound of formulaIV is F. In another embodiment, each of R², R³, and R⁴ of a compound offormula IV is F, and R¹ is CH₂CCH (i.e., C₁₋₄alkyl substituted withR^(1a), wherein R^(1a) is

and R^(1b) is H).

In another further embodiment, each of R² and R³ in a compound offormula IV is H and R⁴ is F.

In one aspect, the compounds of formula (I) are 6-pentafluorophenylbenzoxazinones.

In some variations of the foregoing, the salt may be an agriculturallysuitable salt. In certain variations, the agriculturally suitable saltis a salt that exhibits herbicidal activity, or that is or can beconverted in plants, water, or soil into a compound or salt withherbicidal activity.

In some aspects, provided is a compound selected from the compoundslisted in Table 1 below, or a salt thereof (including an agriculturallysuitable salt thereof).

TABLE 1 Exemplary Compounds

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

In some variations, provided is Compound 1-53 or 56-68, or a saltthereof (including an agriculturally suitable salt thereof). In somevariations, provided is Compound 1-29, or a salt thereof (including anagriculturally suitable salt thereof). In some variations, provided isCompound 1-62, or a salt thereof (including an agriculturally suitablesalt thereof). In one variation, provided is Compound 2, or a saltthereof (including an agriculturally suitable salt thereof). In anothervariation, provided is Compound 37, or a salt thereof (including anagriculturally suitable salt thereof). In another variation, provided isCompound 52, or a salt thereof (including an agriculturally suitablesalt thereof).

Definitions

As used herein, the terms “comprises,” “comprising,” “includes,”“including,” “has,” “having,” “contains,” “containing,” “characterizedby,” or any other variation thereof, are intended to cover anon-exclusive inclusion, subject to any limitation explicitly indicated.For example, a composition, mixture, process, or method that includes orcomprises a list of elements is not necessarily limited to only thoseelements but may include other elements not expressly listed or inherentto such composition, mixture, process, or method.

The transitional phrase “consisting of” excludes any element, step, oringredient not specified. If in the claim, such would close the claim tothe inclusion of materials other than those recited except forimpurities ordinarily associated therewith. When the phrase “consistingof” appears in a clause of the body of a claim, rather than immediatelyfollowing the preamble, it limits only the element set forth in thatclause; other elements are not excluded from the claim as a whole.

Further, unless expressly stated to the contrary, “or” refers to aninclusive ‘or’ and not to an exclusive ‘or.’ For example, a condition Aor B is satisfied by any one of the following: A is true (or present)and B is false (or not present), A is false (or not present) and B istrue (or present), and both A and B are true (or present).

Also, the indefinite articles “a” and “an” preceding an element orcomponent of the invention are intended to be nonrestrictive regardingthe number of instances (i.e. occurrences) of the element or component.Therefore “a” or “an” should be read to include one or at least one, andthe singular word form of the element or component also includes theplural unless the number is obviously meant to be singular.

As referred to herein, the term “seedling,” used either alone or in acombination of words means a young plant developing from the embryo of aseed.

As referred to herein, the term “broadleaf,” used either alone or interms such as “broadleaf weed” means dicot or dicotyledon, a term usedto describe a group of angiosperms characterized by embryos having twocotyledons.

In the above recitations, the term “alkyl,” used either alone or incompound words such as “alkylthio” or “haloalkyl” includesstraight-chain or branched alkyl, such as, methyl, ethyl, n-propyl,i-propyl, or the different butyl, pentyl, or hexyl isomers. “Alkenyl”includes straight-chain or branched alkenes such as ethenyl, 1-propenyl,2-propenyl, and the different butenyl, pentenyl, and hexenyl isomers.“Alkenyl” also includes polyenes such as 1,2-propadienyl and2,4-hexadienyl. “Alkynyl” includes straight-chain or branched alkynessuch as ethynyl, 1-propynyl, 2-propynyl, and the different butynyl,pentynyl, and hexynyl isomers. “Alkynyl” can also include moietiescomprised of multiple triple bonds such as 2,5-hexadiynyl.

“Alkoxy” includes, for example, methoxy, ethoxy, n-propyloxy,isopropyloxy and the different butoxy, pentoxy, and hexyloxy isomers.

“Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

The term “halogen” or “halo” either alone or in compound words such as“haloalkyl,” or when used in descriptions such as “alkyl substitutedwith halogen” includes fluorine, chlorine, bromine, or iodine.

The total number of carbon atoms in a substituent group is indicated bythe “C_(i)-Cj” or “C_(i-j)” prefix, where i and j are numbers from 1 to10. For example, C₁₋₄ alkylsulfonyl designates methylsulfonyl throughbutylsulfonyl; C₂ alkoxyalkyl designates CH₃OCH₂—; C₃ alkoxyalkyldesignates, for example, CH₃CH(OCH₃)—, CH₃OCH₂CH₂—, or CH₃CH₂OCH₂—; andC₄ alkoxyalkyl designates the various isomers of an alkyl groupsubstituted with an alkoxy group containing a total of four carbonatoms, examples including CH₃CH₂CH₂OCH₂- and CH₃CH₂OCH₂CH₂—.

When a compound is substituted with a substituent bearing a subscriptthat indicates the number of said substituents can exceed 1, thesubstituents (when they exceed 1) are independently selected from thegroup of defined substituents, e.g., (R¹)_(m), where m is 0, 1, 2 or 3.Further, when the subscript indicates a range, e.g. (R)_(i-j), then thenumber of substituents may be selected from the integers between ‘i’ and‘j’ inclusive. When a group contains a substituent, which can behydrogen (H), for example, then when this substituent is taken ashydrogen, it is recognized that this is equivalent to the group beingunsubstituted. When a variable group is shown to be optionally attachedto a position, then hydrogen may be at the position even if not recitedin the variable group definition. When one or more positions on a groupare said to be “not substituted” or “unsubstituted,” then hydrogen atomsare attached to take up any free valency.

Unless otherwise indicated, a “ring” or “ring system” as a component ofa compound of the invention, is carbocyclic or heterocyclic.

“Aromatic” indicates that each of the ring atoms is essentially in thesame plane and has a p-orbital perpendicular to the ring plane, and that(4n+2) π electrons, where n is a positive integer, are associated withthe ring to comply with Hückel's rule. The term “aromatic ring system”denotes a carbocyclic or heterocyclic ring system in which at least onering of the ring system is aromatic.

The term “nonaromatic ring system” denotes a carbocyclic or heterocyclicring system that may be fully saturated, as well as partially or fullyunsaturated, provided that none of the rings in the ring system arearomatic.

The term “optionally substituted” in connection with the heterocyclicrings refers to groups which are unsubstituted or have at least onenon-hydrogen substituent that does not extinguish the biologicalactivity possessed by the unsubstituted analog. As used herein, thefollowing definitions shall apply unless otherwise indicated. The term“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted” or with the term “(un)substituted.”Unless otherwise indicated, an optionally substituted group may have asubstituent at each substitutable position of the group, and eachsubstitution is independent of the other.

The term “acceptable salt” or “salt” when related to a compound of theinvention includes cations or anions. Preferred cations are the ions ofthe alkali metals, preferably of lithium, sodium and potassium, of thealkaline earth metals, preferably of calcium and magnesium, and of thetransition metals, preferably of manganese, copper, zinc and iron,further ammonium and substituted ammonium in which one to four hydrogenatoms are replaced by C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, phenyl, orbenzyl—preferably ammonium, methylammonium, isopropylammonium,dimethylammonium, diethylammonium, diisopropylammonium,trimethylammonium, triethylammonium, tris(isopropyl)ammonium,heptylammonium, dodecylammonium, tetradecylammonium,tetramethylammonium, tetraethylammonium, tetrabutylammonium,2-hydroxyethylammonium (olamine salt),2-(2-hydroxyeth-1-oxy)eth-1-ylammonium (diglycolamine salt),di(2-hydroxyeth-1-yl)ammonium (diolamine salt),tris(2-hydroxyethyl)ammonium (trolamine salt),tris(2-hydroxypropyl)ammonium, benzylthmethylammonium,benzyltriethylammonium, N,N,N-trimethylethanolammonium (choline salt),furthermore phosphonium ions, sulfonium ions, preferablytri(C₁-C₄-alkyl)sulfonium, such as trimethylsulfonium, and sulfoxoniumions, preferably tri(C₁-C₄-alkyl)sulfoxonium, and finally the salts ofpolybasic amines such as N,N-bis-(3-aminopropyl)methylamine, anddiethylenetriamine.

Anions of useful acid addition salts are primarily chloride, bromide,fluoride, iodide, hydrogensulfate, methylsulfate, sulfate,dihydrogenphosphate, hydrogenphosphate, nitrate, bicarbonate, carbonate,hexafluorosilicate, hexafluorophosphate, benzoate, and also the anionsof C₁-C₄-alkanoic acids—preferably formate, acetate, propionate, andbutyrate.

As used herein, the terms “undesirable vegetation” and “harmful plants”are synonyms.

Preparation of Compounds of the Invention

A wide variety of synthetic methods are known in the art to enablepreparation of aromatic and nonaromatic heterocyclic rings and ringsystems; for extensive reviews see the eight volume set of ComprehensiveHeterocyclic Chemistry, A. R. Katritzky and C. W. Rees editors-in-chief,Pergamon Press, Oxford, 1984 and the twelve-volume set of ComprehensiveHeterocyclic Chemistry II, A. R. Katritzky, C. W. Rees and E. F. V.Scriven editors-in-chief, Pergamon Press, Oxford, 1996.

Compounds of the invention can exist as one or more stereoisomers. Thevarious stereoisomers include enantiomers, diastereomers, atropisomers,and geometric isomers. Stereoisomers are isomers of identicalconstitution but differing in the arrangement of their atoms in spaceand include enantiomers, diastereomers, cis-trans isomers (also known asgeometric isomers) and atropisomers. Atropisomers result from restrictedrotation about single bonds where the rotational barrier is high enoughto permit isolation of the isomeric species. One skilled in the art willappreciate that one stereoisomer may be more active and/or may exhibitbeneficial effects when enriched relative to the other stereoisomer(s)or when separated from the other stereoisomer(s). Additionally, theskilled artisan knows how to separate, enrich, and/or to selectivelyprepare said stereoisomers. The compounds of the invention may bepresent as a mixture of stereoisomers, individual stereoisomers or as anoptically active form. For a comprehensive discussion of all aspects ofstereoisomerism, see Ernest L. Eliel and Samuel H. Stereochemistry ofOrganic Compounds, John Wiley & Sons, New York, 1994. Compounds of theinvention typically exist in more than one form, and the formulas of theinvention thus include all crystalline and non-crystalline forms of thecompounds they represent. Non-crystalline forms include embodimentswhich are solids such as waxes and gums as well as embodiments which areliquids such as solutions and melts. Crystalline forms includeembodiments which represent essentially a single crystal type andembodiments which represent a mixture of polymorphs (i.e. differentcrystalline types). The term “polymorph” refers to a particularcrystalline form of a chemical compound that can crystallize indifferent crystalline forms, these forms having different arrangementsand/or conformations of the molecules in the crystal lattice. Althoughpolymorphs can have the same chemical composition, they can also differin composition due the presence or absence of co-crystallized water orother molecules, which can be weakly or strongly bound in the lattice.Polymorphs can differ in such chemical, physical, and biologicalproperties as crystal shape, density, hardness, color, chemicalstability, melting point, hygroscopicity, suspensibility, dissolutionrate, and biological availability. One skilled in the art willappreciate that a polymorph of a compound of the invention can exhibitbeneficial effects (e.g., suitability for preparation of usefulformulations, improved biological performance) relative to anotherpolymorph or a mixture of polymorphs of the same compound. Preparationand isolation of a particular polymorph of a compound of a compound ofthe invention can be achieved by methods known to those skilled in theart including, for example, crystallization using selected solvents andtemperatures. For a comprehensive discussion of polymorphism see R.Hilfiker, Ed., Polymorphism in the Pharmaceutical Industry, Wiley-VCH,Weinheim, 2006.

One skilled in the art recognizes that because in the environment andunder physiological conditions salts of chemical compounds are inequilibrium with their corresponding nonsalt forms, salts share thebiological utility of the nonsalt forms. Thus, a wide variety of saltsof compounds of the invention are useful for control of undesiredvegetation (i.e. are agriculturally suitable). The salts of compounds ofthe invention include acid-addition salts with inorganic or organicacids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric,acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic,salicylic, tartaric, 4-toluenesulfonic, or valeric acids. When acompound of the invention contains an acidic moiety such as a carboxylicacid or phenol, salts also include those formed with organic orinorganic bases such as pyridine, triethylamine, or ammonia, or amides,hydrides, hydroxides or carbonates of sodium, potassium, lithium,calcium, magnesium, or barium.

Moreover, the invention features processes and intermediates forpreparing compounds of the invention. These compounds can be prepared bygeneral methods known in the art of synthetic organic chemistry. One ormore of the following methods and variations as described in Schemes 1a,1b, & 2 can be used.

In one general example, the compounds of formula I can be prepared asshown in Scheme Ta.

Accordingly, compounds of formula c can be prepared by reaction of acompound of formula a, where X is Br or I, with a substituted phenyl offormula b using cross-coupling reaction conditions with the aid of ametal catalyst as shown in Step 1 of Scheme Ta. Suitable catalystsinclude palladium catalysts, such as Pd(OAc)₂ combined with2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos). As shown inStep 2 of Scheme Ta, compounds of formula d can be prepared bydemethylation of the aryl methyl ether of a compound of formula c underacidic conditions. In one example, a Lewis acid such as boron tribromidecan be used. As shown in Step 3 of Scheme 1a, compounds of formula e canbe prepared by reduction of the nitro group of a compound of formula d.Several methods for this are known to those skilled in the art,including the use of catalytic hydrogenation, sodium sulfide, or sodiumhydrosulfite. As shown in Step 4 of Scheme 1a, compounds of formula gcan be prepared by condensing the amino group of a compound of formula ewith a suitable haloacetate of formula f under basic conditions in anorganic solvent. In one example, the base is a trialkylamine such astriethylamine or diisopropylethylamine. As shown in Step 5 of Scheme 1a,benzoxazinones of formula h (a compound of formula I, wherein R¹ is H)can be prepared via intramolecular ring closure between the phenolichydroxyl group and N-acyl halide of a compound of formula g in asuitable polar organic solvent such as DMF or DMSO. As shown in Step 6of Scheme 1a, a compound of formula I (wherein R¹ is, for example, anoptionally substituted C₁₋₄alkyl) can be formed by reacting thebenzoxazinone amino group of a compound of formula h with an alkyl oraryl halide of formula i under conditions suitable for bond formation.Alternatively, a compound of formula h can be reacted with a boronicacid of formula j using a Chan-Lam type coupling to form a compound offormula I.

In another general example, the compounds of formula I can be preparedas shown in Scheme 1b.

Accordingly, phenyl boronic acids (where R═H) or phenyl boronates (e.g.,where —B(OR)₂ represents a pinacol ester) of formula j can be coupled toa suitably substituted phenyl bromide or iodide in a Suzuki-Miyaura-typereaction using a suitable catalyst to produce a compound of formula c(Step 1). This can also be accomplished under similar conditions byreacting a compound for formula k with a compound m (Step 2). Employingsteps analogous to Steps 2 to 6 as described in Scheme 1 can then beused to transform a compound of formula c to a compound of formula I.Alternatively, a compound of formula n can be reacted with a compound offormula o (Step 3) or a compound of formula p can be reacted with acompound of formula q (Step 4) under Suzuki conditions to produce acompound of formula I.

In yet another general example, the compounds of formula I can beprepared as shown in Scheme 2.

Accordingly, as shown in Step 1 of Scheme 2, a fluorinated phenylcompound of formula r, where L is a leaving group such as Br, I, or OTf(triflate), is reacted with a compound of formula s, where M¹ is analkali metal such as Li, or is MgBr such as found in Grignard reagents,to produce a compound of formula v. Alternatively, as shown in Step 2 ofScheme 2, a compound of formula v is produced by reacting a compound offormula t, where L is a leaving group such as Br or I, with a compoundof formula u under conditions suitable for Cu-mediated aryl-aryl crosscoupling known to those skilled in the art. The compound of formula vcan then be nitrated, as shown in Step 3 of Scheme 2, followed bycarrying out Steps 2 to 6 of Scheme 1a to produce a compound of formulaI.

In one aspect, provided is a method of preparing a compound of formula(I) as described herein, or a salt thereof, comprising:

-   -   deprotecting a compound of formula (c), or a salt thereof, to        yield a compound of formula (d), or a salt thereof,

-   -   reducing a compound of formula (d), or a salt thereof, to yield        a compound of formula (e), or a salt thereof,

-   -   reacting a compound of formula (e), or a salt thereof, with a        compound of formula (f), or a salt thereof, to yield a compound        of formula (g), or a salt thereof,

-   -   cyclizing a compound of formula (g), or a salt thereof, to yield        a compound of formula (h), or a salt thereof,

and

-   -   reacting a compound of formula (h), or a salt thereof, with a        compound of formula (i), or a salt thereof, to yield a compound        of formula (I), or a salt thereof,

wherein:

-   -   Y is X or B(OH)₂;    -   X is Br or I; and    -   R¹-R⁸, and ring A are as defined herein for formula (I).

In some embodiments, the compound of formula (c), or a salt thereof, isprepared according to a process comprising reacting a compound offormula (a), or a salt thereof, with a compound of formula (b), or asalt thereof, to yield a compound of formula (c), or a salt thereof,

In some embodiments, the compound of formula (c), or a salt thereof, isprepared according to a process comprising reacting a compound offormula (a), or a salt thereof, with a compound of formula (j), or asalt thereof, to yield a compound of formula (c), or a salt thereof,

wherein R is H or phenyl.

In some embodiments, the compound of formula (c), or a salt thereof, isprepared according to a process comprising reacting a compound offormula (k), or a salt thereof, with a compound of formula (m), or asalt thereof, to yield a compound of formula (c), or a salt thereof,

In some embodiments, the compound of formula (c), or a salt thereof, isprepared according to a process comprising reacting a compound offormula (v), or a salt thereof, to yield a compound of formula (c), or asalt thereof,

In some embodiments, the compound of formula (v), or a salt thereof, isprepared according to a process comprising reacting a compound offormula (r), or a salt thereof, with a compound of formula (s), or asalt thereof, to yield a compound of formula (v), or a salt thereof,

wherein L is Br, I, or OTf; and M¹ is an alkali metal.

In some embodiments, the compound of formula (v), or a salt thereof, isprepared according to a process comprising reacting a compound offormula (t), or a salt thereof, with a compound of formula (u), or asalt thereof, to yield a compound of formula (v), or a salt thereof,

wherein L is Br, I, or OTf, and M² is an alkali metal.

In one aspect, provided is a method of preparing a compound of formula(I), or a salt thereof, comprising reacting a compound of formula (p),or a salt thereof, with a compound of formula (q), or a salt thereof, toform a compound of formula (I), or a salt thereof,

wherein:

-   -   R is H or phenyl;    -   X is Br or I; and    -   R¹-R⁸, and ring A are as defined herein for formula (I).

In one aspect, provided is a method of preparing a compound of formula(I), or a salt thereof, comprising reacting a compound of formula (n),or a salt thereof, with a compound of formula (o), or a salt thereof, toform a compound of formula (I), or a salt thereof,

wherein:

-   -   R is H or phenyl;    -   X is Br or I; and    -   R¹-R⁸, and ring A are as defined herein for formula (I).

In another aspect, provided is a compound of formula (a), or a saltthereof,

wherein X is Br or I, and R⁴ is as defined for formula (I).

In another aspect, provided is a compound of formula (b), or a saltthereof,

wherein R⁶-R⁸ and Ring A are as defined for formula (I).

In another aspect, provided is a compound of formula (c), or a saltthereof,

wherein R⁴-R⁸ and Ring A are as defined for formula (I).

In one embodiment, the compound of formula (c) is

In another aspect, provided is a compound of formula (d), or a saltthereof,

wherein R⁴-R⁸ and Ring A are as defined for formula (I).

In one embodiment, the compound of formula (d) is

In another aspect, provided is a compound of formula (e), or a saltthereof,

wherein R⁴-R⁸ and Ring A are as defined for formula (I).

In one embodiment, the compound of formula (e) is

In another aspect, provided is a compound of formula (f), or a saltthereof,

wherein R² and R³ are as defined for formula (I).

In another aspect, provided is a compound of formula (g), or a saltthereof,

wherein R⁴-R⁸ and Ring A are as defined for formula (I).

In one embodiment, the compound of formula (g) is

In another aspect, provided is a compound of formula (h), or a saltthereof,

wherein R²-R⁸ and Ring A are as defined for formula (I).

In another aspect, provided is a compound of formula (i), or a saltthereof,

wherein Y is X or B(OH)₂; X is Br or I; and R¹ is as defined for formula(I).

In another aspect, provided is a compound of formula (j), or a saltthereof,

wherein R⁶-R⁸ and Ring A are as defined for formula (I).

In another aspect, provided is a compound of formula (k), or a saltthereof,

wherein R⁴ and R⁵ are as defined for formula (I).

In another aspect, provided is a compound of formula (m), or a saltthereof,

wherein R⁶-R⁸ and Ring A are as defined for formula (I).

In another aspect, provided is a compound of formula (n), or a saltthereof,

wherein X is Br or I, and R¹-R⁵ are as defined for formula (I).

In one embodiment, the compound of formula (n) is or

In another aspect, provided is a compound of formula (o), or a saltthereof,

wherein R is H or phenyl, and R⁶-R⁸ and Ring A are as defined forformula (I).

In another aspect, provided is a compound of formula (p), or a saltthereof,

wherein R is H or phenyl, and R¹-R⁵ are as defined for formula (I).

In another aspect, provided is a compound of formula (q), or a saltthereof,

wherein X is Br or I; and R⁶-R⁸ and Ring A are as defined for formula(I).

In another aspect, provided is a compound of formula (r), or a saltthereof,

wherein L is Br, I, or OTf, and R⁶-R⁸ and Ring A are as defined forformula (I).

In another aspect, provided is a compound of formula (s), or a saltthereof,

wherein M¹ is an alkali metal, and R¹, R⁴, and R⁵ are as defined forformula (I).

In another aspect, provided is a compound of formula (t), or a saltthereof,

wherein L is Br, I, or OTf, and R⁴-R⁵ are as defined for formula (I).

In another aspect, provided is a compound of formula (u), or a saltthereof,

wherein M² is an alkali metal; and R⁶-R⁸ and Ring A are as defined forformula (I).

In another aspect, provided is a compound of formula (v), or a saltthereof,

wherein R⁴-R⁸ and Ring A are as defined for formula (I).

Any of the embodiments and variations described herein for formula (I)also applies to intermediates of formulae (a), (b), (c), (d), (e), (f),(g), (h), (i), (j), (k), (1), (m), (n), (o), (p), (q), (r), (s), (t),(u), or (v).

It is recognized by one skilled in the art that various functionalgroups can be converted into others to provide different compounds ofthe invention. For a valuable resource that illustrates theinterconversion of functional groups in a simple and straightforwardfashion, see Larock, R. C, Comprehensive Organic Transformations: AGuide to Functional Group Preparations, 2^(nd) Ed., Wiley-VCH, New York,1999.

It is recognized that some reagents and reaction conditions describedabove for preparing compounds of the invention may not be compatiblewith certain functionalities present in the intermediates. In theseinstances, the incorporation of protection/deprotection sequences orfunctional group interconversions into the synthesis will aid inobtaining the desired products. The use and choice of the protectinggroups will be apparent to one skilled in chemical synthesis (see, forexample, Greene, T. W.; Wuts, P. G. M., Protective Groups in OrganicSynthesis, 2^(nd) ed.; Wiley: New York, 1991). One skilled in the artwill recognize that, in some cases, after the introduction of a givenreagent as depicted in any individual scheme, it may be necessary toperform additional routine synthetic steps not described in detail tocomplete the synthesis of compounds of the invention. One skilled in theart will also recognize that it may be necessary to perform acombination of the steps illustrated in the above schemes in an orderother than that implied by the particulars presented to prepare thecompounds of the invention.

One skilled in the art will also recognize that compounds of theinvention and the intermediates described herein can be subjected tovarious electrophilic, nucleophilic, radical, organometallic, oxidation,and reduction reactions to add substituents or modify existingsubstituents.

Compositions

In certain aspects, a compound of this disclosure, including anagriculturally suitable salt thereof, may be used as an herbicidalactive ingredient in a formulation, with at least one additionalcomponent selected from the group consisting of surfactants, soliddiluents, and liquid diluents, which serves as a carrier. Theformulation ingredients are selected to be consistent with the physicalproperties of the active ingredient, mode of application, andenvironmental factors such as soil type, moisture, and temperature.

In some variations, the compositions provided here are herbicides. Insome variations, the compositions comprise a compound of this disclosurethat controls or modifies the growth of plants. In certain variations,the compositions comprise a herbicidally effective amount of thecompound, such that the quantity of such compound is capable ofproducing a controlling or modifying effect on the growth of plants.Controlling or modifying effects include all deviation from naturaldevelopment, for example killing, retardation, leaf burn, albinism,dwarfing and the like.

Liquid formulations include solutions (including emulsifiableconcentrates), suspensions, emulsions (including microemulsions,oil-in-water emulsions, flowable concentrates and/or suspoemulsions),and the like, which optionally can be thickened into gels. The generaltypes of aqueous liquid formulations are soluble concentrate, suspensionconcentrate, capsule suspension, concentrated emulsion, microemulsion,oil-in-water emulsion, flowable concentrate, and suspoemulsion. Thegeneral types of nonaqueous liquid formulations are emulsifiableconcentrate, microemulsifiable concentrate, dispersible concentrate, andoil dispersion.

The general types of solid formulations are dusts, powders, granules,pellets, prills, pastilles, tablets, filled films (including seedcoatings), and the like, which can be water-dispersible (“wettable”) orwater-soluble. Films and coatings formed from film-forming solutions orflowable suspensions are particularly useful for seed treatment. Activeingredient can be (micro)encapsulated and further formed into asuspension or solid formulation. Alternatively, the entire formulationof active ingredient can be encapsulated (or “overcoated”).Encapsulation can control or delay release of the active ingredient. Anemulsifiable granule combines the advantages of both an emulsifiableconcentrate formulation and a dry granular formulation. High-strengthformulations are primarily used as intermediates for furtherformulation.

Sprayable formulations are typically extended in a suitable mediumbefore spraying. Such liquid and solid formulations are formulated to bereadily diluted in the spray medium, usually water, but occasionallyanother suitable medium like an aromatic or paraffinic hydrocarbon orvegetable oil. Spray volumes can range from about from about one toseveral thousand liters per hectare, but more typically are in the rangefrom about ten to several hundred liters per hectare. Sprayableformulations can be tank mixed with water or another suitable medium forfoliar treatment by aerial or ground application, or for application tothe growing medium of the plant.

Liquid and dry formulations can be metered directly into drip irrigationsystems or metered into the furrow during planting.

The formulations will typically contain effective amounts of activeingredient, diluent, and surfactant within the following approximateranges, shown in Table 2, which add up to 100 percent by weight.

TABLE 2 Formulation Ratios Weight Percent Active Ingredient DiluentSurfactant Water-Dispersible and Water-Soluble 0.001-90  0-99.999 0-15Granules, Tablets, and Powders Oil Dispersions, Suspensions,     1-5040-99 0-50 Emulsions Solutions (including emulsifiable Concentrates)Dusts     1-25 70-99 0-5 Granules and Pellets 0.001-99  5-99.999 0-15High Strength Formulations   90-99  0-10 0-2

Solid diluents include, for example, clays such as bentonite,montmorillonite, attapulgite and kaolin, gypsum, cellulose, titaniumdioxide, zinc oxide, starch, dextrin, sugars (e.g., lactose, sucrose),silica, talc, mica, diatomaceous earth, urea, calcium carbonate, sodiumcarbonate and bicarbonate, and sodium sulfate. Typical solid diluentsare described in Watkins et al., Handbook of Insecticide Dust Diluentsand Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey.

Liquid diluents include, for example, water; N,N-dimethylalkanamides(e.g., N,N-dimethylformamide); limonene; dimethyl sulfoxide;N-alkylpyrrolidones (e.g., N-methylpyrrolidinone); alkyl phosphates(e.g., triethyl phosphate); ethylene glycol; triethylene glycol;propylene glycol; dipropylene glycol; polypropylene glycol; propylenecarbonate; butylene carbonate; paraffins (e.g., white mineral oils,normal paraffins, isoparaffins); alkylbenzenes; alkylnaphthalenes;glycerine; glycerol triacetate; sorbitol; aromatic hydrocarbons;dearomatized aliphatics; alkylbenzenes; alkylnaphthalenes; ketones suchas cyclohexanone, 2-heptanone, isophorone, and4-hydroxy-4-methyl-2-pentanone; acetates such as isoamyl acetate, hexylacetate, heptyl acetate, octyl acetate, nonyl acetate, tridecyl acetate,and isobornyl acetate; other esters such as alkylated lactate esters,dibasic esters, alkyl and aryl benzoates, and γ-butyrolactone; andalcohols, which can be linear, branched, saturated or unsaturated, suchas methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutylalcohol, n-hexanol, 2-ethylhexanol, n-octanol, decanol, isodecylalcohol, isooctadecanol, cetyl alcohol, lauryl alcohol, tridecylalcohol, oleyl alcohol, cyclohexanol, tetrahydrofurfuryl alcohol,diacetone alcohol, cresol, and benzyl alcohol. Liquid diluents alsoinclude glycerol esters of saturated and unsaturated fatty acids(typically C₆-C₂₂) such as plant seed and fruit oils (e.g., oils ofolive, castor, linseed, sesame, corn (maize), peanut, sunflower,grapeseed, safflower, cottonseed, soybean, rapeseed, coconut, and palmkernel), animal-sourced fats (e.g., beef tallow, pork tallow, lard, codliver oil, fish oil), and mixtures thereof. Liquid diluents also includealkylated fatty acids (e.g., methylated, ethylated, butylated) whereinthe fatty acids may be obtained by hydrolysis of glycerol esters fromplant and animal sources and can be purified by distillation. Typicalliquid diluents are described in C. Marsden & S. Mann, Solvents Guide,Cleaver-Hume Press, London, 1963.

The solid and liquid formulations of the present disclosure ofteninclude one or more surfactants. When added to a liquid, surfactants(also known as “surface-active agents”) generally modify, most oftenreduce, the surface tension of the liquid. Depending on the nature ofthe hydrophilic and lipophilic groups in a surfactant molecule,surfactants can be useful as wetting agents, dispersants, emulsifiers,or defoaming agents.

Surfactants can be classified as nonionic, anionic, or cationic.Nonionic surfactants useful for the present formulations include, butare not limited to: alcohol alkoxylates such as alcohol alkoxylatesbased on natural and synthetic alcohols (which may be branched orlinear) and prepared from the alcohols and ethylene oxide, propyleneoxide, butylene oxide or mixtures thereof, amine ethoxylates,alkanolamides, and ethoxylated alkanolamides; alkoxylated triglyceridessuch as ethoxylated soybean, castor, and rapeseed oils; alkylphenolalkoxylates such as octylphenol ethoxylates, nonylphenol ethoxylates,dinonyl phenol ethoxylates, and dodecyl phenol ethoxylates (preparedfrom the phenols and ethylene oxide, propylene oxide, butylene oxide ormixtures thereof); block polymers prepared from ethylene oxide orpropylene oxide and reverse block polymers where the terminal blocks areprepared from propylene oxide; ethoxylated fatty acids; ethoxylatedfatty esters and oils; ethoxylated methyl esters; ethoxylatedtristyrylphenol (including those prepared from ethylene oxide, propyleneoxide, butylene oxide, or mixtures thereof); fatty acid esters, glycerolesters, lanolin-based derivatives, polyethoxylate esters such aspolyethoxylated sorbitan fatty acid esters, polyethoxylated sorbitolfatty acid esters, and polyethoxylated glycerol fatty acid esters; othersorbitan derivatives such as sorbitan esters; polymeric surfactants suchas random copolymers, block copolymers, alkyd PEG (polyethylene glycol)resins, graft or comb polymers and star polymers; polyethylene glycols(PEGs); polyethylene glycol fatty acid esters; silicone-basedsurfactants; and sugar-derivatives such as sucrose esters, alkylpolyglycosides, and alkyl polysaccharides.

Useful anionic surfactants include, but are not limited to: alkylarylsulfonic acids and their salts; carboxylated alcohol or alkylphenolethoxylates; diphenyl sulfonate derivatives; lignin and ligninderivatives such as lignosulfonates; maleic or succinic acids or theiranhydrides; olefin sulfonates; phosphate esters such as phosphate estersof alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates andphosphate esters of styryl phenol ethoxylates; protein-basedsurfactants; sarcosine derivatives; styryl phenol ether sulfate;sulfates and sulfonates of oils and fatty acids; sulfates and sulfonatesof ethoxylated alkylphenols; sulfates of alcohols; sulfates ofethoxylated alcohols; sulfonates of amines and amides such asN,N-alkyltaurates; sulfonates of benzene, cumene, toluene, xylene, anddodecyl and tridecylbenzenes; sulfonates of condensed naphthalenes;sulfonates of naphthalene and alkyl naphthalene; sulfonates offractionated petroleum; sulfosuccinamates; and sulfosuccinates and theirderivatives such as dialkyl sulfosuccinate salts.

Useful cationic surfactants include, but are not limited to: amides andethoxylated amides; amines such as N-alkyl propanediamines,tripropylenetriamines, and dipropylenetetramines, and ethoxylatedamines, ethoxylated diamines and propoxylated amines (prepared from theamines and ethylene oxide, propylene oxide, butylene oxide or mixturesthereof); amine salts such as amine acetates and diamine salts;quaternary ammonium salts such as quaternary salts, ethoxylatedquaternary salts, and diquaternary salts; and amine oxides such asalkyldimethylamine oxides and bis-(2-hydroxyethyl)-alkylamine oxides.

Also useful for the present formulations are mixtures of nonionic andanionic surfactants or mixtures of nonionic and cationic surfactants.Nonionic, anionic, and cationic surfactants and their recommended usesare disclosed in a variety of published references includingMcCutcheon's Emulsifiers andDetergents, annual American andInternational Editions published by McCutcheon's Division, TheManufacturing Confectioner Publishing Co.; Sisely and Wood, Encyclopediaof Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964; andA. S. Davidson and B. Milwidsky, Synthetic Detergents, Seventh Edition,John Wiley and Sons, New York, 1987.

Formulations of the present invention may also contain formulationauxiliaries and additives, known to those skilled in the art asformulation aids (some of which may be considered to also function assolid diluents, liquid diluents, or surfactants). Such formulationauxiliaries and additives may control the following: pH (buffers),foaming during processing (antifoams such polyorganosiloxanes),sedimentation of active ingredients (suspending agents), viscosity(thixotropic thickeners), in-container microbial growth(antimicrobials), product freezing (antifreezes), color (dyes/pigmentdispersions), wash-off (film formers or stickers), evaporation(evaporation retardants), and other formulation attributes. Film formersinclude, for example, polyvinyl acetates, polyvinyl acetate copolymers,polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols,polyvinyl alcohol copolymers, and waxes. Examples of formulationauxiliaries and additives include those listed in McCutcheon's Volume 2:Functional Materials, annual International and North American editionspublished by McCutcheon's Division, The Manufacturing ConfectionerPublishing Co.; and PCT Publication WO 03/024222.

The compounds of the invention and any other active ingredients aretypically incorporated into the present formulations by dissolving theactive ingredient in a solvent or by grinding in a liquid or drydiluent. Solutions, including emulsifiable concentrates, can be preparedby simply mixing the ingredients. If the solvent of a liquidformulations intended for use as an emulsifiable concentrate iswater-immiscible, an emulsifier is typically added to emulsify theactive-containing solvent upon dilution with water. Active ingredientslurries, with particle diameters of up to 2,000 microns can be wetmilled using media mills to obtain particles with average diametersbelow 3 microns. Aqueous slurries can be made into finished suspensionconcentrates (see, for example, U.S. Pat. No. 3,060,084) or furtherprocessed by spray drying to form water-dispersible granules. Dryformulations usually require dry milling processes, which produceaverage particle diameters in the 2 micron to 10 micron range. Dusts andpowders can be prepared by blending and usually grinding (such as with ahammer mill or fluid-energy mill). Granules and pellets can be preparedby spraying the active material upon preformed granular carriers or byagglomeration techniques. See Browning, “Agglomeration,” ChemicalEngineering, Dec. 4, 1967, pp 147-48, Perry's Chemical Engineer'sHandbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 andfollowing, and PCT Publication WO 91/13546. Pellets can be prepared asdescribed in U.S. Pat. No. 4,172,714. Water-dispersible andwater-soluble granules can be prepared as taught in U.S. Pat. Nos.4,144,050 and 3,920,442 and German Pat. No. 3,246,493. Tablets can beprepared as taught in U.S. Pat. Nos. 5,180,587, 5,232,701, and5,208,030. Films can be prepared as taught in Great Britain Pat. No.2,095,558 and U.S. Pat. No. 3,299,566.

For further information regarding the art of formulation, see T. S.Woods, “The Formulator's Toolbox—Product Forms for Modern Agriculture”in Pesticide Chemistry and Bioscience, The Food-Environment Challenge,T. Brooks and T. R. Roberts, Eds., Proceedings of the 9th InternationalCongress on Pesticide Chemistry, The Royal Society of Chemistry,Cambridge, 1999, pp. 120-133. See also U.S. Pat. No. 3,235,361, Col. 6,line 16 through Col. 7, line 19 and Examples 10-41; U.S. Pat. No.3,309,192, Col. 5, line 43 through Col. 7, line 62 and Examples 8, 12,15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182;U.S. Pat. No. 2,891,855, Col. 3, line 66 through Col. 5, line 17 andExamples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons,Inc., New York, 1961, pp 81-96; Hance et al., Weed Control Handbook, 8thEd., Blackwell Scientific Publications, Oxford, 1989; and Developmentsin formulation technology, PJB Publications, Richmond, UK, 2000.

Biological Activity

Test results indicate that the compounds of the present invention arehighly active preemergent and/or postemergent herbicides and/or plantgrowth regulants. The compounds of the invention generally show highestactivity for postemergence weed control (e.g., applied after weedseedlings emerge from the soil) and preemergence weed control (e.g.,applied before weed seedlings emerge from the soil). Many of them haveutility for broad-spectrum pre- and/or postemergence weed control inareas where complete control of all vegetation is desired such as aroundfuel storage tanks, industrial storage areas, parking lots, drive-intheaters, airfields, riverbanks, irrigation, and other waterways, aroundbillboards and highway and railroad structures. Many of the compounds ofthis disclosure, by virtue of selective metabolism in crops versusweeds, or by selective activity at the locus of physiological inhibitionin crops and weeds, or by selective placement on or within theenvironment of a mixture of crops and weeds, are useful for theselective control of grass and broadleaf weeds within a crop/weedmixture. One skilled in the art will recognize that the preferredcombination of these selectivity factors within a compound or group ofcompounds can readily be determined by performing routine biologicaland/or biochemical assays.

In some variations, provided herein is a method of controlling undesiredvegetation, comprising applying a compound of formula I, II, III or IV,or a salt thereof (including an agriculturally suitable salt thereof).In some variations, the compound is applied at low application rates. Incertain variations, the compound is applied at a rate of 1 to 10,000 gper 10,000 m², 2 to 5,000 g per 10,000 m², 5 to 2,000 g per 10,000 m², 1to 1000 g per 10,000 m², 1 to 500 g per 10,000 m², 1 to 100 g per 10,000m², 1 to 75 g per 10,000 m², 15 to 1000 g per 10,000 m², 15 to 100 g per10,000 m², 15 to 75 g per 10,000 m², or 15 to 60 g per 10,000 m². Incertain variations of the foregoing, the application of the compound atthe aforementioned application rates leads to postemergence control ofthe undesired vegetation and/or preemergence control of the undesiredvegetation.

In certain variations, the application of the compound, including at theaforementioned application rate, leads to burndown. In one variation,burndown refers to when an herbicide is used to reduce weed presence atthe time of treatment. Burndown is often used in minimum or no-tillfields because the weeds cannot be managed by tilling the soil. Theburndown application may be used post-harvest and/or prior to cropemergence. Burndown may be useful against weeds that emerge betweengrowing seasons.

In certain variations, the application of the compound, including at theaforementioned application rate, imparts residual control. The compoundsdescribed herein may be used as pre-emergence herbicides, which may beapplied after crop planting, but prior to crop and/or weed emergence.Herbicides considered pre-emergence also may be referred to as thoseimparting “residual control,” and provide extended control ofgerminating or newly emerged weeds

In one variation, the undesired vegetation is at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90%, at least 95%, at least 96%, at least97%, at least 98%, at least 99%, or about 100% controlled. In somevariations of the foregoing, the undesired vegetation is a weed. In onevariation, the undesired vegetation is a PPO inhibitor-resistant weed.

Examples of crop fields treated by the compounds in the presentinvention include edible crop fields such as peanut fields, soybeanfields, corn fields, and wheat fields, feed crop fields such as sorghumfields and oat fields, industrial crop fields such as cotton fields andrape fields, and sugar crop fields such as sugarcane fields and sugarbeet fields. In one variation, crop fields treated by the compoundsherein include corn, soybean, wheat, and cotton fields.

Examples of vegetable fields treated by the compounds in the presentinvention include fields for cultivation of solanaceous vegetables(eggplants, tomatoes, bell peppers, capsicums, potatoes, and the like),fields for cultivation of cucurbitaceous vegetables (cucumbers,pumpkins, zucchini, watermelons, melons, and the like), fields forcultivation of cruciferous vegetables (radishes, turnips, horseradishes,kohlrabies, Chinese cabbages, cabbages, mustard, broccolis,cauliflowers, and the like), fields for cultivation of asteraceousvegetables (burdocks, garland chrysanthemums, artichokes, lettuces, andthe like), fields for cultivation of liliaceous vegetables (leeks,onions, garlics, and asparagus), fields for cultivation of apiaceousvegetables (carrots, parsley, celery, parsnips, and the like), fieldsfor cultivation of chenopodiaceous vegetables (spinach, chards, and thelike), fields for cultivation of lamiaceous vegetables (perilla, mint,basil, and lavender), strawberry fields, sweet potato fields, yamfields, and taro fields.

Examples of the land under perennial crops in the present inventioninclude orchards, tea fields, mulberry fields, coffee fields, bananafields, palm fields, flowering tree firms, flowering tree fields,planting stock fields, nursery fields, forest lands, and gardens.Examples of the orchard trees in the present invention include pomaceousfruits (apples, pears, Japanese pears, Chinese quinces, quinces, and thelike), stone fruits (peaches, plums, nectarines, Japanese apricots,cherries, apricots, prunes, and the like), citrus fruits (Citrus unshiu,oranges, lemons, limes, grapefruits, and the like), nut trees(chestnuts, walnuts, hazelnut trees, almonds, pistachios, cashew nuttrees, macadamia nut trees, and the like), berry fruits (grapes,blueberries, cranberries, blackberries, raspberries, and the like),Japanese persimmons, olives, and loquats.

Examples of the non-crop land in the present invention include athleticfields, empty lots, railroad edges, parks, parking lots, road edges, dryriverbeds, lands under a power line, residential lands, and factorysites.

The crop cultivated in the crop field in the present invention is notlimited as long as the crop is a variety generally cultivated as a crop.

The plant of the above-mentioned variety may be a plant that can beproduced by natural crossing, a plant that can be generated by mutation,an F1 hybrid plant, or a transgenic plant (also referred to as agenetically-modified plant). The plant generally has properties such asobtaining of the tolerance to an herbicide, accumulation of a toxicsubstance against a pest, suppression of the susceptibility to adisease, increase in the yield potential, improvement in the toleranceto a biotic and an abiotic stressors, accumulation of a substance, andimprovement in the preservability and the processability.

An F1 hybrid plant is a first-generation hybrid obtained by crossingvarieties of two different strains, and generally has a heteroticproperty with a trait superior to that of either of the parents. Atransgenic plant has a foreign gene introduced from another organism orthe like such as a microorganism and has a property that cannot beeasily obtained by cross breeding, mutagenesis, or natural recombinationin a natural environment.

Examples of the techniques for producing the above-mentioned plantsinclude conventional breeding techniques; genetic engineeringtechniques; genome breeding techniques; new breeding techniques; andgenome editing techniques. Conventional breeding techniques are forobtaining a plant having a desirable property by mutation or crossing.Genetic engineering techniques include techniques for imparting a newproperty to a target organism by extracting a target gene (DNA) fromanother organism (for example, a microorganism) and introducing thetarget gene into the genome of the target organism. Genetic engineeringtechniques also include antisense techniques or RNA interferencetechniques for imparting a new or improved property by silencing anothergene present in the plant. Genome breeding techniques are for improvingbreeding efficiency using genomic information, and examples of thegenome breeding techniques include DNA marker (also called genomicmarker or genetic marker) breeding techniques and genomic selection. Forexample, DNA marker breeding is a method in which a progeny having atarget useful trait gene is selected from a large number of crossedprogenies using a DNA marker that is a DNA sequence that serves as amarker of the location of the specific useful trait gene on the genome.In the method, the crossed progeny is analyzed when it is an infantplant using a DNA marker to effectively shorten the time required forthe breeding.

Genomic selection is a technique in which a prediction formula iscreated from a phenotype and genomic information obtained in advance topredict the property from the prediction formula and the genomicinformation without evaluating the phenotype and is a technique that cancontribute to improving breeding efficiency. The term “new breedingtechniques” is a general term for breed improvement (breeding)techniques that combine molecular biological techniques. Examples of thenew breeding techniques include cisgenesis/intragenesis,oligonucleotide-directed mutagenesis, RNA-dependent DNA methylation,genome editing, grafting on a GM rootstock or a scion, reverse breeding,agroinfiltration, and seed production technology (SPT). The genomeediting technique is for converting genetic information in asequence-specific manner, and it is possible to delete a base sequence,substitute an amino acid sequence, introduce a foreign gene, and thelike using the technique. Examples of the tool include sequence-specificgenome modification techniques such as a zinc finger nuclease capable ofsequence-specific DNA cleavage (Zinc-Finger, ZFN), TALEN, CRISPR-Cas9,CRISPER-Cpf1, Meganuclease, and CAS9 Nickase and Target-AID created bymodifying the aforementioned tools.

Examples of the above-mentioned plants include plants listed in thedatabase of the registered genetically-modified crops (GM ApprovalDatabase) in the electronic information site of International Servicefor the Acquisition of Agri-biotech Applications (ISAAA)(http://www.isaaa.org/). More specific examples are herbicide-tolerantplants, pest-resistant plants, disease-resistant plants, plants modifiedin the quality (for example, with increase or decrease in the content orchange in the composition) of the products (for example, starch, aminoacids, and fatty acids), fertility trait-modified plants, abioticstress-tolerant plants, and plants modified in the trait related to thegrowth or the yield.

Mechanisms of obtaining herbicide tolerance include reduction in theaffinity between the agent and its target, rapid metabolism(decomposition, modification, and the like) of the agent by an expressedenzyme that inactivates the agent, or inhibition of incorporation ortranslocation of the agent in the plant body. Examples of the plants towhich herbicide tolerance has been imparted by genetic engineeringtechnique include plants to which tolerance has been imparted to4-hydroxyphenylpyruvate dioxygenase (hereinafter abbreviated as HPPD)inhibitors such as isoxaflutole and mesotrione, acetolactate synthase(hereinafter abbreviated as ALS) inhibitors such as imidazolinoneherbicides containing imazethapyr and sulfonylurea herbicides containingthifensulfuron-methyl, 5-enolpyruvylshikimate-3-phosphate synthase(hereinafter abbreviated as EPSP) inhibitors such as glyphosate,glutamine synthase inhibitors such as glufosinate, auxin herbicides suchas 2,4-D and dicamba, and oxynyl herbicides containing bromoxynil.Preferable herbicide-tolerant transgenic plants treated by thecombinations of the invention are cereals such as wheat, barley, rye,and oats, canola, sorghum, soybeans, rice, rape, sugar beet, sugar cane,grapes, lentils, sunflowers, alfalfa, pomaceous fruits, drupes, coffee,tea, strawberries, lawn grass, tomatoes, potatoes, cucumbers, andvegetables such as lettuces, and more preferable herbicide-toleranttransgenic plants are cereals such as wheat, barley, rye, and oats,soybeans, rice, vines, tomatoes, potatoes, and pomaceous fruits.

In one example, in order to obtain the glyphosate herbicide-tolerantplants one or more genes are introduced from: a glyphosate-tolerantEPSPS gene (CP4 epsps) from Agrobacterium tumefaciens strain CP4; aglyphosate metabolizing enzyme gene (gat4601, gat4621) in which themetabolic activity of the glyphosate metabolizing enzyme (glyphosateN-acetyltransferase) gene from Bacillus licheniformis is enhanced by ashuffling technique; a glyphosate metabolizing enzyme (glyphosateoxidase gene, goxv247) from Ochrobacterum anthropi strain LBAA; andEPSPS genes from maize having a glyphosate-tolerant mutation (mepsps,2mepsps). Main examples of the plants are alfalfa (Medicago sativa),Argentine canola (Brassica napus), cotton (Gossypium hirsutum L.),creeping bentgrass (Agrostis stolonfera), maize (Zea mays L.), polishcanola (Brassica rapa), potato (Solanum tuberosum L.), soybean (Glycinemax L.), sugar beet (Beta vulgaris), and wheat (Triticum aestivum). Someglyphosate-tolerant transgenic plants are commercially available. Forexample, the genetically-modified plant in which the glyphosate-tolerantEPSPS from the Agrobacterium is expressed is commercially available witha trade name such as “Roundup Ready®” the genetically-modified plant inwhich the glyphosate metabolizing enzyme that is from Bacillus and hasthe metabolic activity enhanced by a shuffling technique is expressed iscommercially available with a trade name such as “Optimum® GAT®, or“Optimum® Gly canola”, and the genetically-modified plant in which theEPSPS that is from maize and has glyphosate-tolerant mutation isexpressed is commercially available with the trade name “GlyTol®”.

In another example, in order to obtain the glufosinateherbicide-tolerant plants one or more genes are introduced from: aphosphinothricin N-acetyltransferase (PAT) gene (bar) that is aglufosinate metabolizing enzyme from Streptomyces hygroscopicus; aphosphinothricin N-acetyltransferase (PAT) enzyme gene (pat) that is aglufosinate metabolizing enzyme from Streptomyces viridochromogenes; anda synthesized pat gene (pat syn) from Streptomyces viridochromogenesstrain Tu494. Main examples of the plants include Argentine canola(Brassica napus), chicory (Cichorium intybus), cotton (Gossypiumhirsutum L.), maize (Zea mays L.), polish canola (Brassica rapa), rice(Oryza sativa L.), soybean (Glycine max L.), and sugar beet (Betavulgaris). Some glufosinate-tolerant genetically-modified plants arecommercially available. For example, a genetically-modified plant from aglufosinate metabolizing enzyme (bar) from Streptomyces hygroscopicusand from Streptomyces viridochromogenes is commercially available withtrade names such as “LibertyLink®”, “InVigor®”, or “WideStrike®”.

In another example, oxynil herbicide-tolerant plants are known. Forexample, bromoxynil-tolerant transgenic plants into which a nitrilasegene (bxn) is introduced from an oxynil herbicide metabolizing enzymefrom Klebsiella pneumoniae subsp. ozaenae. Main examples of the plantsare Argentine canola (Brassica napus), cotton (Gossypium hirsutum L.),and tobacco (Nicotiana tabacum L.). The plants are commerciallyavailable with a trade name such as “Navigator® canola” or “BXN®”.

ALS herbicide-tolerant plants are also known. Examples includecarnations (Dianthus caryophyllus), which are obtained by introductionof an ALS herbicide-tolerant ALS gene (surB) as a selection marker fromtobacco (Nicotiana tabacum) and are commercially available with thetrade names “Moondust®”, “Moonshadow®”, “Moonshade®”, “Moonlite®”,“Moonaqua®”, “Moonvista®”, “Moonique®”, “Moonpearl®”, “Moonberry®”, and“Moonvelvet®”; flax (Linum usitatissumum L.), into which an ALSherbicide-tolerant ALS gene (als) from Arabidopsis thaliana isintroduced is commercially available with the trade name “CDC TriffidFlax”; sulfonylurea herbicide-tolerant and an imidazolinoneherbicide-tolerant maize (Zea mays L.) into which an ALSherbicide-tolerant ALS gene (zm-hra) from maize is introduced iscommercially available with the trade name “Optimum® GAT™”; animidazolinone herbicide-tolerant soybean into which an ALSherbicide-tolerant ALS gene (csr1-2) from Arabidopsis thaliana isintroduced is commercially available with the trade name “Cultivance®”;and sulfonylurea herbicide-tolerant soybeans into which an ALSherbicide-tolerant ALS gene (gm-hra) from a soybean (Glycine max) isintroduced are commercially available with the trade names “Treus®”,“Plenish®”, and “Optimum® GAT™”. There is also cotton into which an ALSherbicide-tolerant ALS gene (S4-HrA) from tobacco (Nicotiana tabacum cv.Xanthi) is introduced.

HPPD herbicide-tolerant plants are also known. In one example, a soybeaninto which a mesotrione-tolerant HPPD gene (avhppd-03) from an oat(Avena sativa) and a phinothricin N-acetyltransferase (PAT) enzyme gene(pat) are simultaneously introduced. In another example, a soybeantolerant to mesotrione into which a glufosinate metabolizing enzyme fromStreplomyces viridochromogenes is introduced is commercially available.

In another example, 2,4-D-tolerant plants include: maize into which anaryloxyalkanoate dioxygenase gene (aad-1) for a 2,4-D metabolizingenzyme from Sphingobium herbicidovorans is introduced is commerciallyavailable with the trade name “Enlist® Maize”; and soybean and cottoninto which an aryloxyalkanoate dioxygenase gene (aad-12) for a 2,4-Dmetabolizing enzyme from Delftia acidovorans is introduced iscommercially available with the trade name “Enlist® Soybean”.

In another example, Dicamba-tolerant plants include: soybean and cottoninto which a dicamba monooxygenase gene (dmo) having a dicambametabolizing enzyme from Stenotrophomonas maltophilia strain DI-6 isintroduced; and a soybean (Glycine max L.) into which aglyphosate-tolerant EPSPS gene (CP4 epsps) from Agrobacteriumtumefaciens strain CP4 is introduced simultaneously with theabove-mentioned gene is commercially available with the trade name“Genuity® Roundup Ready™ 2 Xtend®”.

Further examples of the commercially available transgenic plants towhich herbicide tolerance has been imparted include: theglyphosate-tolerant maize “Roundup Ready® Corn”, “Roundup Ready® 2”,“Agrisure® GT”, “Agrisure® GT/CB/LL”, “Agrisure® GT/RW”, “Agrisure®3000GT”, “YieldGard™ VT™ Rootworm/RR2”, and “YieldGard™ VT™ Triple”; theglyphosate-tolerant soybeans “Roundup Ready® Soybean” and “Optimum®GAT”; the glyphosate-tolerant cotton “Roundup Ready® Cotton” and“Roundup Ready® Flex”; the glyphosate-tolerant canola “Roundup Ready®Canola”; the glyphosate-tolerant alfalfa “Roundup Ready® Alfalfa”, theglyphosate-tolerant rice “Roundup Ready® Rice”; the glufosinate-tolerantmaize “Roundup Ready® 2”, “LibertyLink®”, “Herculex® 1”, “Herculex® RW”,“Herculex® Xtra”, “Agrisure® GT/CB/LL”, “Agrisure® CB/LL/RW”, and“Bt10”; the glufosinate-tolerant cotton “FiberMax™ LibertyLink™”; theglufosinate-tolerant canola “InVigor®”; the glufosinate-tolerant rice“LibertyLink™ Rice” (manufactured by Bayer AG); the bromoxynil-tolerantcotton “BXN”; the bromoxynil-tolerant canola “Navigator®” and“Compass®”; and the glufosinate-tolerant canola “InVigor®”. Additionalplants modified with respect to a herbicide are widely known, and theexamples of the plants include alfalfa, apples, barley, eucalyptuses,flax, grapes, lentils, rape, peas, potatoes, rice, sugar beet,sunflowers, tobacco, tomato, turfgrass, and wheat that are tolerant toglyphosate (see, for example, U.S. Pat. Nos. 5,188,642, 4,940,835,5,633,435, 5,804,425, and 5,627,061); beans, cotton, soybeans, peas,potatoes, sunflowers, tomatoes, tobacco, maize, sorghum, and sugar canethat are tolerant to dicamba (see, for example, WO2008051633, U.S. Pat.Nos. 7,105,724, and 5,670,454); soybeans, sugar beet, potatoes,tomatoes, and tobacco that are tolerant to glufosinate (see, forexample, U.S. Pat. Nos. 6,376,754, 5,646,024, and 5,561,236); cotton,peppers, apples, tomatoes, sunflowers, tobacco, potatoes, maize,cucumbers, wheat, soybeans, sorghum, and cereals that are tolerant to2,4-D (see, for example, U.S. Pat. Nos. 6,153,401, 6,100,446,WO2005107437, U.S. Pat. Nos. 5,608,147, and 5,670,454); and canola,maize, millet, barley, cotton, mustard, lettuces, lentils, melons,millet, oats, sword beans, potatoes, rice, rye, sorghum, soybeans, sugarbeet, sunflowers, tobacco, tomatoes, and wheat that are tolerant toacetolactate synthase (ALS) inhibitor herbicide (for example, asulfonylurea herbicide and an imidazolinone herbicide) (see, forexample, U.S. Pat. No. 5,013,659, WO2006060634, U.S. Pat. Nos.4,761,373, 5,304,732, 6,211,438, 6,211,439, and 6,222,100). The ricetolerant to an imidazolinone herbicide is especially known, and examplesof the rice include rice having specific mutation (for example, S653N,S654K, A122T, S653(At)N, S654(At)K, and A122(At)T) in the acetolactatesynthase gene (acetohydroxyacid synthase gene) (see, for example, US2003/0217381, and WO200520673); and the examples include barley, sugarcane, rice, maize, tobacco, soybeans, cotton, rape, sugar beet, wheat,and potatoes that are tolerant to an HPPD inhibitor herbicide (forexample, an isoxazole herbicide such as isoxaflutole, a triketoneherbicide such as sulcotrione or mesotrione, a pyrazole herbicide suchas pyrazolynate, or diketonitrile that is a decomposition product ofisoxaflutole) (see, for example, WO2004/055191, WO199638567,WO1997049816, and U.S. Pat. No. 6,791,014).

Examples of the plants to which herbicide tolerance has been imparted bya classical technique or a genome breeding technique include the rice“Clearfield® Rice”, the wheat “Clearfield® Wheat”, the sunflower“Clearfield® Sunflower”, the lentil “Clearfield® lentils”, and thecanola “Clearfield® canola” (manufactured by BASF SE) that are tolerantto an imidazolinone-based ALS inhibitor herbicide such as imazethapyr orimazamox; the soybean “STS® soybean” that is tolerant to asulfonyl-based ALS inhibitor herbicide such as thifensulfuron-methyl;the sethoxydim-tolerant maize “SR® corn” and ‘Poast Protected® corn”that are tolerant to an acetyl-CoA carboxylase inhibitor such as atrionoxime herbicide or an aryloxy phenoxypropionic acid herbicide; thesunflower “ExpressSun®” that is tolerant to a sulfonylurea herbicidesuch as tribenuron; the rice “Provisia™ Rice” that is tolerant to anacetyl-CoA carboxylase inhibitor such as quizalofop; and the canola“Triazine Tolerant Canola” that is tolerant to a PSII inhibitor.

Examples of the plants to which herbicide tolerance has been imparted bya genome editing technique include the canola “SU Canola®” tolerant to asulfonylurea herbicide in which a rapid variety development technique(Rapid Trait Development System, RTDS®) is used. RTDS® corresponds tooligonucleotide-directed mutagenesis of the genome editing technique,and by RTDS, it is possible to introduce mutation in a DNA in a plantvia Gene Repair Oligonucleotide (GRON), that is, a chimericoligonucleotide of the DNA and the RNA without cutting the DNA. Inaddition, examples of the plants include maize in which herbicidetolerance and phytic acid content have been reduced by deleting theendogenous gene IPK1 using zinc finger nuclease (see, for example,Nature 459, 437-441 2009); and rice to which herbicide tolerance hasbeen imparted using CRISPR-Cas9 (see, for example, Rice, 7, 5 2014).

In the present invention, examples of the crop tolerant to a specificPPO inhibitor include crops to which PPO having a reduced affinity forthe inhibitor is imparted by a genetic engineering technique.Alternatively, the crop may have a substance that detoxifies anddecomposes the PPO inhibitor by cytochrome P450 monooxygenase alone orin combination with the above-mentioned PPO. The tolerant crops aredescribed in, for example, patent documents such as WO2011085221,WO2012080975, WO2014030090, WO2015022640, WO2015022636, WO2015022639,WO2015092706, WO2016203377, WO2017198859, WO2018019860, WO2018022777,WO2017112589, WO2017087672, WO2017039969, and WO2017023778, andnon-patent document Li & Nicholl in Pest Management Science (2005), Vol.61, pgs. 277-285.

Examples of the plants to which herbicide tolerance has been imparted bya new breeding technique in which the property of a GM rootstock isimparted to a scion by a breeding technique in which grafting is usedinclude the non-transgenic soybean scion to which glyphosate toleranceis imparted using the glyphosate-tolerant soybean Roundup Ready® as arootstock (see Jiang, et al., in Weed Technology (2013) Vol. 27, pgs.412-416).

The above-mentioned plants include strains to which two or more traitsare imparted among abiotic stress tolerance, disease resistance,herbicide tolerance, pest resistance, a growth trait, a yield trait,nutrient uptake, product quality, a fertility trait, and the like asdescribed above using a genetic engineering technique, a classicalbreeding technique, a genome breeding technique, a new breedingtechnique, a genome editing technique, or the like, and strains to whichtwo or more of the properties of the parent strains are imparted bycrossing plants having the same or different properties.

Examples of the commercially available plants to which tolerance to twoor more herbicides are imparted include the cotton “GlyTol™LibertyLink™” and “GlyTol™ LibertyLink™” that are tolerant to glyphosateand glufosinate; the maize “Roundup Ready™ LibertyLink™ Maize” that istolerant to glyphosate and glufosinate; the soybean “Enlist™ Soybean”that is tolerant to glufosinate and 2,4-D; the soybean “Genuity® RoundupReady (trademark) 2 Xtend (trademark)” that is tolerant to glyphosateand dicamba; the maize and the soybean “OptimumGAT™” that are tolerantto glyphosate and an ALS inhibitor; the genetically modified soybeans“Enlist E3™” and “Enlist™ Roundup Ready® 2 Yield” that are tolerant tothree herbicides of glyphosate, glufosinate, and 2,4-D; the geneticallymodified maize “Enlist™ Roundup Ready® Corn 2” that is tolerant toglyphosate, 2,4-D, and an aryloxyphenoxypropionate (FOPs) herbicide; thegenetically modified maize “Enlist™ Roundup Ready® Corn 2” that istolerant to glyphosate, 2,4-D, and an aryloxyphenoxypropionate (FOPs)herbicide; the genetically modified cotton “Bollgard II® XtendFlex™Cotton” that is tolerant to dicamba, glyphosate, and glufosinate; andthe genetically modified cotton “Enlist™ Cotton” that is tolerant tothree herbicides of glyphosate, glufosinate, and 2,4-D. In addition, thecotton tolerant to glufosinate and 2,4-D, the cotton tolerant to bothglufosinate and dicamba, the maize tolerant to both glyphosate and2,4-D, the soybean tolerant to both glyphosate and an HPPD herbicide,and the genetically modified maize tolerant to glyphosate, glufosinate,2,4-D, an aryloxyphenoxypropionate (FOPs) herbicide, and acyclohexanedione (DIMs) herbicide have been also developed.

Examples of the commercially available plants to which herbicidetolerance and pest resistance are imparted include the maize “YieldGardRoundup Ready®” and “YieldGard Roundup Ready® 2” that are tolerant toglyphosate and resistant to a corn borer; the maize “Agrisure® CB/LL”that is tolerant to glufosinate and resistant to a corn borer; the maize“Yield Gard® VT Root worm/RR2” that is tolerant to glyphosate andresistant to a corn rootworm; the maize “Yield Gard® VT Triple” that istolerant to glyphosate and resistant to a corn rootworm and a cornborer; the maize “Herculex® I” that is tolerant to glufosinate andresistant to a lepidopteran maize pest (CryiF) (for example, resistanceto a western bean cutworm, a corn borer, a black cutworm, and a fallarmyworm); the maize “YieldGard® Corn Rootworm/Roundup Ready® 2” that istolerant to glyphosate and resistant to a corn rootworm; the maize“Agrisure® GT/RW” that is tolerant to glufosinate and resistant to aColeoptera maize pest (Cry3A) (for example, resistant to a western cornrootworm, a northern corn rootworm, and a Mexican corn rootworm); themaize “Herculex® RW” that is tolerant to glufosinate and resistant to aColeoptera maize pest (Cry34/35Abl) (for example, resistant to a westerncorn rootworm, a northern corn rootworm, and a Mexican corn rootworm);the maize “Yield Gard® VT Root worm/RR2” that is tolerant to glyphosateand resistant to a corn rootworm; and the cotton “Bollgard 3®XtendFlex®” that is tolerant to dicamba, glyphosate, and glufosinate andresistant to a lepidopteran cotton pest (for example, resistant tobollworms, a tobacco budworm, and armyworms).

In the present invention, a composition of the invention is applied to aplace where weeds are growing or likely to grow. Examples of the methodof applying the present composition include a method of spraying thepresent composition on soil and a method of spraying the presentcomposition on weeds.

In some variations, the application rate of a composition of theinvention is generally 1 to 10,000 g per 10,000 m², 2 to 5,000 g per10,000 m², 5 to 2,000 g per 10,000 m², 1 to 1000 g per 10,000 m², 1 to500 g per 10,000 m², 1 to 100 g per 10,000 m², 1 to 75 g per 10,000 m²,15 to 1000 g per 10,000 m², 15 to 100 g per 10,000 m², 15 to 75 g per10,000 m², or 15 to 60 g per 10,000 m², in terms of the total amount ofa compound of formula I, II, III or IV, or a salt thereof (including anagriculturally suitable salt thereof).

In one variation, the application rate of a composition of the inventionis generally 1 to 10,000 g per 10,000 m², 2 to 5,000 g per 10,000 m², 5to 2,000 g per 10,000 m², 1 to 1000 g per 10,000 m², 1 to 500 g per10,000 m², 1 to 100 g per 10,000 m², 1 to 75 g per 10,000 m², 15 to 1000g per 10,000 m², 15 to 100 g per 10,000 m², 15 to 75 g per 10,000 m², or15 to 60 g per 10,000 m², in terms of the total amount of a compound offormula I and the at least one compound selected from the groupconsisting of the herbicide compound group B and the safener group C.

In the present method, an adjuvant may be mixed in a composition of theinvention, followed by application. The type of the adjuvant is notparticularly limited, and examples of the adjuvant include oil-basedadjuvants such as Agri-Dex® and methylated seed oil (MSO), non-ions(esters or ethers of polyoxyethylene) such as Induce, anions(substituted sulfonates) such as Gramine S, cations (polyoxyethyleneamines) such as Genamin® T 200BM, and organic silicons such as Silwet®L77.

The pH and the hardness of the spray liquid prepared when a compositionof the invention is applied are not particularly limited, and the pH isusually in the range of 5 to 9, and the hardness is usually in the rangeof 0 to 500.

The time period for applying a composition of the invention is notparticularly limited, and is usually in the range of 5:00 AM to 9:00 PM,and the photon flux density is usually 10 to 2,500 μmol/m²/s.

When a composition of the invention is applied to a crop field, it maybe applied before sowing a crop seed, simultaneously with sowing a cropseed, and/or after sowing a crop seed. That is, the frequency of theapplication of a composition of the invention is once before,simultaneously with, or after sowing a crop seed, twice excluding beforethe sowing, excluding simultaneously with the sowing, or excluding afterthe sowing, or three times at all the timing.

When a composition of the invention is applied before sowing a cropseed, it is applied from 50 days before to immediately before thesowing, preferably from 30 days before to immediately before the sowing,more preferably from 20 days before to immediately before the sowing,and still more preferably from 10 days before to immediately before thesowing.

When a composition of the invention is applied after sowing a crop seed,it is usually applied from immediately after the sowing to beforeflowering. The composition is more preferably applied from immediatelyafter the sowing to before the emergence, or from 1 to 6 leaf stages ofthe crop. The case where a composition of the invention is appliedsimultaneously with sowing a crop seed is the case where a sowingmachine and a sprayer are integrated with each other.

In the step of applying a composition of the invention in a cultivationarea, a compound of formula I or the compound and at least oneadditional compound selected from the group consisting of the herbicidecompound group B and the safener group C are usually mixed with acarrier such as a solid carrier or a liquid carrier, and an auxiliaryagent for formulation such as a surfactant is added if necessary toprepare a formulation. Preferable formulation types is aqueous liquidsuspension formulations, oil-based suspension formulations, wettablepowders, water dispersible granules, granules, water-based emulsions,oil-based emulsions, and emulsifiable concentrates, and more preferableformulation type is emulsifiable concentrates. Furthermore, aformulation containing a compound of formula I alone as an activeingredient and a formulation containing the at least one compoundselected from the group consisting of the herbicide compound group B andthe safener group C as an active ingredient may be used in combination.Furthermore, a formulation containing the present composition as activeingredients and a formulation containing another herbicide as an activeingredient may be used in combination.

Examples of the method of applying a composition of the invention in acultivation area include a method of spraying it on the soil in thecultivation area and a method of spraying the present composition on aweeds that are growing. The composition is usually diluted with water,followed by spraying. The spray volume is not particularly limited, andis usually 50 to 1,000 L/ha, preferably 100 to 500 L/ha, and morepreferably 140 to 300 L/ha.

Specific examples of the weed species to be controlled by the presentcomposition include, but are not limited to, the weed species describedbelow.

Urticaceae weeds to be controlled include Urtica urens.

Polygonaceae weeds to be controlled include Polygonum convolvulus,Polygonum lapathifolium, Polygonum pensylvanicum, Polygonum persicaria,Polygonum longisetum, Polygonum aviculare, Polygonum arenastrum,Polygonum cuspidatum, Rumex japonicus, Rumex crispus, Rumexobtusifolius, and Rumex acetosa.

Portulacaceae weeds to be controlled include Portulaca oleracea.

Caryophyllaceae weeds to be controlled include Stellaria media,Stellaria aquatica, Cerastium holosteoides, Cerastium glomeratum,Spergula arvensis, and Silene gallica.

Molluginaceae weeds to be controlled include Mollugo verticillate.

Chenopodiaceae weeds to be controlled include Chenopodium album,Chenopodium ambrosioides, Kochia scoparia, Salsola kali, and Atriplexspp.

Amaranthaceae weeds to be controlled include Amaranthus retroflexus,Amaranthus viridis, Amaranthus lividus, Amaranthus spinosus, Amaranthushybridus, Amaranthus palmeri, Amaranthus patulus, Waterhemp (Amaranthustuberculatus, Amaranthus rudis, or Amaranthus tamariscinus), Amaranthusblitoides, Amaranthus deflexus, Amaranthus quitensis, Alternantheraphiloxeroides, Alternanthera sessilis, and Alternanthera tenella.

Papaveraceae weeds to be controlled include Papaver rhoeas, Papaverdubium, and Argemone Mexicana.

Brassicaceae weeds to be controlled include Raphanus raphanistrum,Raphanus sativus, Sinapis arvensis, Capsella bursa-pastoris, Brassicajuncea, Brassica napus, Descurainia pinnata, Rorippa islandica, Rorippasylvestris, Thlaspi arvense, Myagrum rugosum, Lepidium virginicum, andCoronopus didymus.

Capparaceae weeds to be controlled include Cleome affinis.

Fabaceae weeds to be controlled include Aeschynomene indica,Aeschynomene rudis, Sesbania exaltata, Cassia obtusifolia, Cassiaoccidentalis, Desmodium tortuosum, Desmodium adscendens, Desmodiumillinoense, Trifolium repens, Pueraria lobata, Vicia angustifolia,Indigofera hirsuta, Indigofera truxillensis, and Vigna sinensis.

Oxalidaceae weeds to be controlled include Oxalis corniculata, Oxalisstrica, and Oxalis oxyptera.

Geraniaceae weeds to be controlled include Geranium carolinense andErodium cicutarium.

Euphorbiaceae weeds to be controlled include Euphorbia helhoscopia,Euphorbia maculata, Euphorbia humistrata, Euphorbia esula, Euphorbiaheterophylla, Euphorbia brasiliensis, Acalypha australis, Crotonglandulosus, Croton lobatus, Phyllanthus corcovadensis, and Ricinuscommunis.

Malvaceae weeds to be controlled include Abutilon theophrasti, Sidarhombiforia, Sida cordifolia, Sida spinosa, Sida glaziovii, Sidasantaremnensis, Hibiscus trionum, Anoda cristata, and Malvastrumcoromandelianum.

Onagraceae weeds to be controlled include Ludwigia epilobioides,Ludwigia octovalvis, Ludwigia decurre, Oenothera biennis, and Oenotheralaciniata.

Sterculiaceae weeds to be controlled include Waltheria indica.

Violaceae weeds to be controlled include Viola arvensis and Violatricolor.

Cucurbitaceae weeds to be controlled include Sicyos angulatus,Echinocystis lobata, and Momordica charantia.

Lythraceae weeds to be controlled include Ammannia multiflora, Ammanniaauriculata, Ammannia coccinea, Lythrum salicaria, and Rotala indica.

Elatinaceae weeds to be controlled include Elatine triandra and Elatinecalifornica.

Apiaceae weeds to be controlled include Oenanthe javanica, Daucuscarota, and Conium maculatum.

Araliaceae weeds to be controlled include Hydrocotyle sibthorpioides andHydrocotyle ranunculoides.

Ceratophyllaceae weeds to be controlled include Ceratophyllum demersum.

Cabombaceae weeds to be controlled include Cabomba caroliniana.

Haloragaceae weeds to be controlled include Myriophyllum aquaticum,Myriophyllum verticillatum, Myriophyllum spicatum, and Myriophyllumheterophyllum.

Sapindaceae weeds to be controlled include Cardiospermum halicacahum.

Primulaceae weeds to be controlled include Anagallis arvensis.

Asclepiadaceae weeds to be controlled include Asclepias syriaca, andAmpelamus albidus.

Rubiaceae weeds to be controlled include Galium aparine, Galium spuriumvar. echinospermon, Spermacoce latifolia, Richardia brasiliensis, andBorreria alata.

Convolvulaceae weeds to be controlled include Ipomoea nil, Ipomoeahederacea, Ipomoea purpurea, Ipomoea hederacea var. integriuscula,Ipomoea lacunosa, Ipomoea triloba, Ipomoea acuminata, Ipomoeahederifolia, Ipomoea coccinea, Ipomoea quamoclit, Ipomoea grandifolia,Ipomoea aristolochiafolia, Ipomoea cairica, Convolvulus arvensis,Calystegia hederacea, Calystegia japonica, Merremia hedeacea, Merremiaaegyptia, Merremia cissoides, and Jacquemontia tamnfolia.

Boraginaceae weeds to be controlled include Myosotis arvensis.

Lamiaceae weeds to be controlled include Lamium purpureum, Lamiumamplexicaule, Leonotis nepetaefolia, Hyptis suaveolens, Hyptis lophanta,Leonrus sibiricus, and Stachys arvensis.

Solanaceae weeds to be controlled include Datura stramonium, Solanumnigrum, Solanum americanum, Solanum ptycanthum, Solanum sarrachoides,Solanum rostratum, Solanum aculeatissimum, Solanum sisymbriifolium,Solanum carolinense, Physalis angulata, Physalis subglabrata, andNicandra physaloides.

Scrophulariaceae weeds to be controlled include Veronica hederaefolia,Veronica persica, Veronica arvensis, Lindernia procumbens, Linderniadubia, Lindernia angustifolia, Bacopa rotundifolia, Dopatrium junceum,and Gratiola japonica.

Plantaginaceae weeds to be controlled include Plantago asiatica,Plantago lanceolata, Plantago major, and Callitriche palustris.

Asteraceae weeds to be controlled include Xanthium pensylvanicum,Xanthium occidentale, Xanthium italicum, Helianthus annuus, Matricariachamomilla, Matricaria perforata, Chrysanthemum segetum, Matricariamatricarioides, Artemisia princeps, Artemisia vulgaris, Artemisiaverlotorum, Solidago altissima, Taraxacum officinale, Galinsoga ciliata,Galinsoga parviflora, Senecio vulgaris, Senecio brasiliensis, Seneciogrisebachii, Conyza bonariensis, Conyza smatrensis, Conyza canadensis,Ambrosia artemisiaefolia, Ambrosia trifida, Bidens tripartita, Bidenspilosa, Bidens frondosa, Bidens subalternans, Cirsium arvense, Cirsiumvulgare, Silybum marianum, Carduus nutans, Lactuca serriola, Sonchusoleraceus, Sonchus asper, Wedelia glauca, Melampodium perfoliatum,Emilia sonchifolia, Tagetes minuta, Blainvillea latifolia, Tridaxprocumbens, Porophyllum ruderale, Acanthospermum ausirale,Acanihospermum hispidum, Cardiospermum halicacabum, Ageratum conyzoides,Eupatorium perfoliatum, Eclipta alba, Erechtites hieracifolia,Gamochaeta spicata, Gnaphalium spicatum, Jaegeria hirta, Partheniumhysterophorus, Siegesbeckia orientalis, Soliva sessilis, Ecliptaprostrata, Eclipta alba, and Centipeda minima.

Alismataceae weeds to be controlled include Sagittaria pygmaea,Sagittaria trifolia, Sagittaria sagittifolia, Sagittaria montevidensis,Sagittaria aginashi, Alisma canaliculatum, and Alisma plantago-aquatica.

Limnocharitaceae weeds to be controlled include Limnocharis flava.

Hydrocharitaceae weeds to be controlled include Limnobium spongia,Hydrilla verticillata, and Najas guadalupensis.

Araceae weeds to be controlled include Pistia stratiotes.

Lemnaceae weeds to be controlled include Lemna aoukikusa, Spirodelapolyrhiza, and Wolffia spp.

Potamogetonaceae to be controlled include Potamogeton distinctus,Potamogeton crispus, Potamogeton illinoensis, and Stuckenia pectinata.

Liliaceae weeds to be controlled include Allium canadense, Alliumvineale, and Allium macrostemon.

Pontederiaceae weeds to be controlled include Eichhornia crassipes,Heteranthera limosa, Monochoria korsakowii, and Monochoria vaginalis.

Commelinaceae weeds to be controlled include Commelina communis,Commelina bengharensis, Commelina erecta, and Murdannia keisak.

Poaceae weeds to be controlled include Echinochloa crus-galli,Echinochloa oryzicola, Echinochloa crus-galli var formosensis,Echinochloa oryzoides, Echinochloa colona, Echinochloa crus-pavonis,Setaria viridis, Setaria faberi, Setaria glauca, Setaria geniculata,Digitaria ciliaris, Digitaria sanguinalis, Digitaria horizontalis,Digitaria insularis, Eleusine indica, Poa annua, Poa trivialis, Poapratensis, Alospecurus aequalis, Alopecurus myosuroides, Avena fatua,Sorghum halepense, Sorghum vulgare, Agropyron repens, Loliummultiflorum, Lolium perenne, Lolium rigidum, Bromus catharticus, Bromussterilis, Bromus japonicus, Bromus secalinus, Bromus tectorum, Hordeumjubatum, Aegilops cylindrica, Phalaris arundinacea, Phalaris minor,Apera spica-venti, Panicum dichotomnflorum, Panicum texanum, Panicummaximum, Brachiaria platyphylla, Brachiaria ruziziensis, Brachiariaplantaginea, Brachiaria decumbens, Brachiaria brizantha, Brachiariahumidicola, Cenchrus echinatus, Cenchrus pauciflorus, Eriochloa villosa,Pennisetum setosum, Chloris gayana, Chlorisvirgata, Eragrostis pilosa,Rhynchelitrum repens, Dactyloctenium aegyptium, Ischaemum rugosum,Isachne globosa, Oryza sativa, Paspalum notatum, Paspalum maritimum,Paspalum distichum, Pennisetum clandestinum, Pennisetum setosum,Rottboellia cochinchinensis, Leptochloa chinensis, Leptochloafascicularis, Leptochloa filiformis, Leptochloa panicoides, Leersiajaponica, Leersia sayanuka, Leersia oryzoides, Glyceria leptorrhiza,Glyceria acutiflora, Glyceria maxima, Agrostis gigantea, Agrostisstolonifera, Cynodon dactylon, Dactylis glomerata, Eremochloaophiuroides, Festuca arundinacea, Festuca rubra, Imperata cylindrica,Miscanthus sinensis, Panicum virgatum, and Zoysia japonica.

Cyperaceae weeds to be controlled include Cyperus microiria, Cyperusiria, Cyperus compressus, Cyperus difjbrmis, Cyperus flaccidus, Cyperusglobosus, Cyperus nipponics, Cyperus odoratus, Cyperus serotinus,Cyperus rotundus, Cyperus esculentus, Kyllinga gracillima, Kyllingabrevifolia, Fimbristylis miliacea, Fimbristylis dichotoma, Eleocharisacicularis, Eleocharis kuroguwai, Schoenoplectiella hotarui,Schoenoplectiella juncoides, Schoenoplectiella wallichii,Schoenoplectiella mucronatus, Schoenoplectiella triangulatus,Schoenoplectiella nipponicus, Schoenoplectiella triqueter, Bolboschoenuskoshevnikovii, and Bolboschoenus fluviatilis.

Equisetaceae weeds to be controlled include Equisetum arvense, andEquisetum palustre.

Salviniaceae weeds to be controlled include Salvinia natans.

Azollaceae weeds to be controlled include Azolla japonica and Azollaimbricata.

Marsileaceae weeds to be controlled include Marsilea quadrifolia.

Other weeds to be controlled include Pithophora, Cladophora, Bryophyta,Marchantiophyta, Anthocerotophyta, Cyanobacteria, Pteridophyta, suckerof perennial crops (pomaceous fruits, nut trees, citruses, Humuluslupulus, grapes, and the like).

In the above-mentioned weeds to be controlled, mutations within thespecies are not particularly limited. That is, the weeds include weedshaving reduced sensitivity to a specific herbicide. The reducedsensitivity may be attributed to a mutation at a target site (targetsite mutation) or may be attributed to any factors other than the targetsite mutation (non-target site mutation). Examples of the factor of thereduced sensitivity due to a non-target site mutation include increasedmetabolism, malabsorption, translocation dysfunction, and excretion toout of system. Examples of the factor of the increased metabolisminclude the enhanced activity of a metabolizing enzyme such ascytochrome P450 monooxygenase, aryl acylamidase, esterase, orglutathione S-transferase. Examples of the excretion to out of systeminclude transport to the vacuole by an ABC transporter. Examples of theweeds having reduced sensitivity due to a target site mutation includeweeds having any one of or two or more of the following amino acidsubstitutions in the ALS gene: Ala122Thr, Ala122Val, Ala122Tyr,Pro197Ser, Pro197His, Pro197Thr, Pro197Arg, Pro197Leu, Pro197Gln,Pro197Ala, Pro197Ile, Ala205Val, Ala205Phe, Asp376Glu, Arg377His,Trp574Leu, Trp574Gly, Trp574Met, Ser653Thr, Ser653Thr, Ser653Asn,Ser635Ile, Gly654Glu, and Gly645Asp. Similarly, examples of the weedshaving reduced sensitivity due to a target site mutation include weedshaving any one of or two or more of the following amino acidsubstitutions in the ACCase gene: Ile1781Leu, Ile1781Val, Ile1781Thr,Trp1999Cys, Trp1999Leu, Ala2004Val, Trp2027Cys, Ile2041Asn, Ile2041Val,Asp2078Gly, Cys2088Arg, Gly2096Ala, and Gly2096Ser.

Similarly, as an example of the weeds having reduced sensitivity due toa target site mutation, PPO inhibitor-resistant weeds having one or moremutations selected from an Arg128Leu mutation, an Arg128Met mutation, anArg128Gly mutation, an Arg128His mutation, a Gly210 deletion mutation,and a Gly399Ala mutation in PPO. The word “PPO” means protoporphyrinogenoxidase. Weeds usually have PPO1 and PPO2 in PPO, and theabove-mentioned mutations may be present in either PPO1 or PPO2 or inboth. The case where weeds have the mutations in PPO2 is preferable. Forexample, the word “Arg128Met” means that the mutation is present in the128th (the number is standardized with PPO2 of Amaranthus palmeri) aminoacid. In PPO2 of Ambrosia artemisiaefolia, the mutation corresponds to amutation in the 98th amino acid (Rousonelos, et al., Weed Science (2012)Vol. 60, pgs. 335-344) and is known as Arg98Leu. In this case, Arg98 isequivalent to Arg128 according to the present invention. The Arg128Metmutation and the Arg128Gly mutation in the PPO of the weed to becontrolled in the present invention are known in Amaranthus palmeri(Giacomini, et al., Pest Management Science (2017) Vol. 73, pgs.1559-1563), the Arg128His mutation is known in Lolium rigidum(Fernandez-Moreno, et al., Weed Science Society of America (WSSA) annualmeeting, 2018), and the Gly399Ala mutation is known in Amaranthuspalmeri (Rangani, et al., WSSA annual meeting, 2018). In the presentinvention, the above-mentioned reported resistant weeds are particularlyeffectively controlled, but particularly effectively controlled weedsare not limited thereto. That is, other weeds having the amino acidmutation are similarly controlled. Not only Amaranthus palmeri having anArg128Leu mutation, an Arg128Met mutation, an Arg128Gly mutation, anArg128His mutation, a Gly210 deletion mutation, or a Gly399Ala mutation,but also, for example, waterhemp having the above-mentioned mutation,Ambrosia artemisiaefolia having the above-mentioned mutation, Loliumrigidum having the above-mentioned mutation, Lolium multiflorum havingthe above-mentioned mutation, and Euphorbia heterophylla having theabove-mentioned mutation are effectively controlled.

Similarly, examples of the weeds having reduced sensitivity due to atarget site mutation include weeds having an amino acid substitutionsuch as Thr102Ile, Pro106Ser, Pro106Ala, or Pro106Leu in the EPSP gene.In particular, Eleusine indica, Lolium multiflorum, Lolium rigidum,Digitaria insularis, waterhemp, Echinochloa colona, and the like whichare resistant to glyphosate and have one or both of the mutations areeffectively controlled. Similarly, examples of the weeds having reducedsensitivity due to a target site include weeds having increased copiesof the EPSP gene and Amaranthus palmeri, waterhemp, Kochia scoparia, andthe like which are resistant to glyphosate and have the mutation areparticularly effectively controlled. Conyza canadensis, Conyzasmatrensis, and Conyza bonariensis which are resistant to glyphosate inwhich an ABC transporter is involved are also effectively controlled.

In the cultivation of a crop according to the present invention, plantnutritional management in general cultivation of a crop can beperformed. The fertilization system may be based on PrecisionAgriculture or may be conventionally uniform one. In addition, anitrogen-fixing bacterium or a mycorrhizal fungus can be inoculated incombination with seed treatment.

Combinations

In certain aspects, controlling effect on weeds is exhibited by using acompound of formula I and a specific compound in combination.

Accordingly, the present invention features—[1] A herbicidal compositionincluding a compound of formula I and at least one compound selectedfrom the group consisting of a herbicide compound group B and a safenergroup C, wherein a weight ratio of a compound of formula I to the atleast one compound selected from the group consisting of the herbicidecompound group B and the safener group C is 1:0.1 to 1:50, and theherbicide compound group B is a group consisting of the following B-1 toB-12:

-   -   B-1 acetolactate synthase inhibitors;    -   B-2 acetyl-CoA carboxylase inhibitors;    -   B-3 protoporphyrinogen IX oxidase inhibitors;    -   B-4 4-hydrophenylpyruvate dioxygenase inhibitors;    -   B-5 phytoene desaturase inhibitors;    -   B-6 photosystem II inhibitors;    -   B-7 very long chain fatty acid synthesis inhibitors;    -   B-8 microtubule formation inhibitors;    -   B-9 auxin herbicides;    -   B-10 enolpyruvylshikimate 3-phosphate synthase inhibitors;    -   B-11 glutamine synthase inhibitors; and    -   B-12 other herbicides (including agriculturally acceptable salts        or derivatives for each of B-1 to B-12).

The present invention also features—[2] the herbicidal compositionaccording to [1], wherein the B-1 is a group consisting of pyrithiobac,pyrithiobac-sodium salt, pyriminobac, pyriminobac-methyl, bispyribac,bispyribac-sodium salt, pyribenzoxim, pyrimisulfan, pyriftalid,triafamone, amidosulfuron, azimsulfuron, bensulfuron,bensulfuron-methyl, chlorimuron, chlorimuron-ethyl, cyclosulfamuron,ethoxysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron,flupyrsulfuron-methyl-sodium, foramsulfuron, halosulfuron,halosulfuron-methyl, imazosulfuron, mesosulfuron, mesosulfuron-methyl,metazosulfuron, nicosulfuron, orthosulfamuron, oxasulfuron,primisulfuron, primisulfuron-methyl, propyrisulfuron, pyrazosulfuron,pyrazosulfuron-ethyl, rimsulfuron, sulfometuron, sulfometuron-methyl,sulfosulfuron, trifloxysulfuron, trifloxysulfuron-sodium salt,chlorsulfuron, cinosulfuron, ethametsulfuron, ethametsulfuron-methyl,iodosulfuron, iodosulfuron-methyl-sodium, iofensulfuron,iofensulfuron-sodium, metsulfuron, metsulfuron-methyl, prosulfuron,thifensulfuron, thifensulfuron-methyl, triasulfuron, tribenuron,tribenuron-methyl, triflusulfuron, triflusulfuron-methyl, tritosulfuron,bencarbazone, flucarbazone, flucarbazone-sodium salt, propoxycarbazone,propoxycarbazone-sodium salt, thiencarbazone, thiencarbazone-methyl,cloransulam, cloransulam-methyl, diclosulam, florasulam, flumetsulam,metosulam, penoxsulam, pyroxsulam, imazamethabenz,imazamethabenz-methyl, imazamox, imazamox-ammonium salt, imazapic,imazapic-ammonium salt, imazapyr, imazapyr-isopropylammonium salt,imazaquin, imazaquin-ammonium, imazethapyr, and imazethapyr-ammoniumsalt (including agriculturally acceptable salts and derivatives thereoffor each);

the B-2 is a group consisting of clodinafop, clodinafop-propargyl,cyhalofop, cyhalofop-butyl, diclofop, diclofop-methyl, fenoxaprop,fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P-ethyl, fluazifop,fluazifop-butyl, fluazifop-P, fluazifop-P-butyl, haloxyfop,haloxyfop-methyl, haloxyfop-P, haloxyfop-P-methyl, metamifop,propaquizafop, quizalofop, quizalofop-ethyl, quizalofop-P,quizalofop-P-ethyl, alloxydim, clethodim, sethoxydim, tepraloxydim,tralkoxydim, and pinoxaden (including agriculturally acceptable saltsand derivatives thereof for each);

the B-3 is a group consisting of azafenidin, oxadiazon, oxadiargyl,carfentrazone, carfentrazone-ethyl, saflufenacil, cinidon,cinidon-ethyl, sulfentrazone, pyraclonil, pyraflufen, pyraflufen-ethyl,butafenacil, fluazolate, fluthiacet, fluthiacet-methyl, flufenpyr,flufenpyr-ethyl, flumiclorac, flumiclorac-pentyl, flumioxazin,pentoxazone, oxyfluorfen, acifluorfen, acifluorfen-sodium salt,aclonifen, chlormethoxynil, chlornitrofen, nitrofen, bifenox,fluoroglycofen, fluoroglycofen-ethyl, fomesafen, fomesafen-sodium salt,lactofen, tiafenacil, and ethyl[3-[2-chloro-4-fluoro-5-(1-methyl-6-trifluoromethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]acetate(including agriculturally acceptable salts and derivatives thereof foreach);

the B-4 is a group consisting of benzobicyclon, bicyclopyrone,mesotrione, sulcotrione, tefuryltrione, tembotrione, isoxachlortole,isoxaflutole, benzofenap, pyrasulfotole, pyrazolynate, pyrazoxyfen,fenquinotrione, topramezone, tolpyralate, lancotrione,lancotrione-sodium salt,2-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide(CAS Registry Number: 1400904-50-8),2-chloro-N-(1-methyl-1H-tetrazol-5-yl)-3-(methylthio)-4-(trifluoromethyl)-benzamide(CAS Registry Number: 1361139-71-0), and4-(4-fluorophenyl)-6-[(2-hydroxy-6-oxo-1-cyclohexene-1-yl)carbonyl]-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione(CAS Registry Number: 1353870-34-4) (including agriculturally acceptablesalts and derivatives thereof for each);

-   -   the B-5 is a group consisting of diflufenican, picolinafen,        beflubutamid, norflurazon, fluridone, flurochloridone, and        flurtamone (including agriculturally acceptable salts and        derivatives thereof for each);    -   the B-6 is a group consisting of ioxynil, ioxynil-octanoate,        bentazone, pyridate, bromoxynil, bromoxynil-octanoate,        chlorotoluron, dimefuron, diuron, linuron, fluometuron,        isoproturon, isouron, tebuthiuron, benzthiazuron,        methabenzthiazuron, propanil, metobromuron, metoxuron,        monolinuron, siduron, simazine, atrazine, propazine, cyanazine,        ametryn, simetryn, dimethametryn, prometryn, terbumeton,        terbuthylazine, terbutryn, trietazine, hexazinone, metamitron,        metribuzin, amicarbazone, bromacil, lenacil, terbacil,        chloridazon, desmedipham, and phenmedipham (including        agriculturally acceptable salts and derivatives thereof for        each);    -   the B-7 is a group consisting of propachlor, metazachlor,        alachlor, acetochlor, metolachlor, S-metolachlor, butachlor,        pretilachlor, thenylchlor, indanofan, cafenstrole, fentrazamide,        dimethenamid, dimethenamid-P, mefenacet, pyroxasulfone,        fenoxasulfone, naproanilide, napropamide, anilofos, flufenacet,        and ipfencarbazone (including agriculturally acceptable salts        and derivatives thereof for each);    -   the B-8 is a group consisting of trifluralin, pendimethalin,        ethalfluralin, benfluralin, oryzalin, prodiamine, butamifos,        dithiopyr, and thiazopyr (including agriculturally acceptable        salts and derivatives thereof for each);    -   the B-9 is a group consisting of 2,4-DB        [4-(2,4-dichlorophenoxy)butyric acid] and its salts or esters        (dimethylammonium salt, isooctyl ester, and choline salt), MCPA        and its salts or esters (dimethylammonium salt, 2-ethylhexyl        ester, isooctyl ester, sodium salt, and choline salt), MCPB,        mecoprop and its salts or esters (dimethylammonium salt,        dioramine salt, ethadyl ester, 2-ethylhexyl ester, isooctyl        ester, methyl ester, potassium salt, sodium salt, trolamine        salt, and choline salt), mecoprop-P and its salts or esters        (dimethylammonium salt, 2-ethylhexyl ester, isobutyl salt,        potassium salt, and choline salt), dichlorprop and its salt or        ester (butotyl ester, dimethylammonium salt, 2-ethylhexyl ester,        isooctyl ester, methyl ester, potassium salt, sodium salt, and        choline salt), dichlorprop-P, dichlorprop-P dimethylammonium,        triclopyr and its salts or esters (butotyl ester, and        triethylammonium salt), fluroxypyr, fluroxypyr-meptyl, picloram        and its salts (potassium salt, tris(2-hydroxypropyl)ammonium        salt, and choline salt), quinclorac, quinmerac, aminopyralid and        its salts (potassium salt, tris(2-hydroxypropyl)ammonium salt,        and choline salt), clopyralid and its salts (olamine salt,        potassium salt, triethylammonium salt, and choline salt),        clomeprop, aminocyclopyrachlor, halauxifen, halauxifen-methyl,        florpyrauxifen, and florpyrauxifen-benzyl (including        agriculturally acceptable salts and derivatives thereof for        each);    -   the B-10 is a group consisting of glyphosate,        glyphosate-isopropylammonium salt, glyphosate-trimesium salt,        glyphosate-ammonium salt, glyphosate-diammonium salt,        glyphosate-dimethylammonium salt, glyphosate-monoethanolamine        salt, glyphosate-sodium salt, glyphosate-potassium salt, and        glyphosate-guanidine salt (including agriculturally acceptable        salts and derivatives thereof for each);    -   B-11 is a group consisting of glufosinate, glufosinate-ammonium        salt, glufosinate-P, glufosinate-P-sodium salt, and bialaphos        (including agriculturally acceptable salts and derivatives        thereof for each); and    -   the B-12 is a group consisting of isoxaben, dichlobenil,        methiozolin, diallate, butylate, triallate, chlorpropham,        asulam, phenisopham, benthiocarb, molinate, esprocarb,        pyributicarb, prosulfocarb, orbencarb, EPTC, dimepiperate, swep,        difenoxuron, methyldymron, bromobutide, daimuron, cumyluron,        diflufenzopyr, diflufenzopyr-sodium salt, etobenzanid,        tridiphane, amitrole, clomazone,        2-[(2,4-dichlorophenyl)methyl]-4,4-dimethylisoxazolidin-3-one        (CAS Registry Number: 81777-95-9),        (3S,4S)—N-(2-fluorophenyl)-1-methyl-2-oxo-4-[3-(trifluoromethyl)phenyl]-3-pyrrolidinecarboxamide        (CAS Registry Number: 2053901-33-8), maleic hydrazide,        oxaziclomefone, cinmethylin, benfuresate, ACN, dalapon,        chlorthiamid, flupoxam, bensulide, paraquat,        paraquat-dichloride, diquat, diquat-dibromide, MSMA, indaziflam,        and triaziflam (including agriculturally acceptable salts and        derivatives thereof for each).

The present invention also features—[3] the herbicidal compositionaccording to [1] or [2], wherein the safener group C is a groupconsisting of benoxacor, cloquintocet, cyometrinil, cyprosulfamide,dichlormid, dicyclonone, dietholate, fenchlorazole, fenclorim,flurazole, fluxofenim, furilazole, isoxadifen, mefenpyr, mephenate,naphthalic anhydride, oxabetrinil,4-(dichloroacetyl)-1-oxa-4-azaspiro[4.5]decane,2,2,5-trimethyl-3-(dichloroacetyl)-1,3-oxazolidine, andN-(2-methoxybenzoyl)-4-[(methylaminocarbonyl)amino]benzenesulfon-amide.

In one embodiment, the present invention includes—[4] the herbicidalcomposition according to [1], wherein B-1 is a group consisting ofpyrithiobac, pyrithiobac-sodium salt, chlorimuron-ethyl, foramsulfuron,halosulfuron-methyl, nicosulfuron, primisulfuron-methyl, rimsulfuron,trifloxysulfuron-sodium salt, chlorsulfuron, iodosulfuron-methyl-sodium,iofensulfuron sodium, metsulfuron-methyl, prosulfuron,thifensulfuron-methyl, tribenuron-methyl, thiencarbazone-methyl,cloransulam-methyl, flumetsulam, imazamethabenz-methyl,imazamox-ammonium salt, imazapic-ammonium salt,imazapyr-isopropylammonium, imazaquin-ammonium salt, andimazethapyr-ammonium salt (including agriculturally acceptable salts andderivatives thereof for each).

In another embodiment, the present invention includes—[5] the herbicidalcomposition according to [1], wherein B-2 is a group consisting offenoxaprop-ethyl, fenoxaprop-P-ethyl, fluazifop-butyl,fluazifop-P-butyl, quizalofop-ethyl, quizalofop-P-ethyl, clethodim, andsethoxydim (including agriculturally acceptable salts and derivativesthereof for each).

In another embodiment, the present invention includes—[6] the herbicidalcomposition according to [1], wherein B-3 is a group consisting ofcarfentrazone-ethyl, saflufenacil, sulfentrazone, pyraflufen-ethyl,fluthiacet-methyl, flufenpyr-ethyl, flumiclorac-pentyl, flumioxazin,oxyfluorfen, acifluorfen-sodium salt, fomesafen-sodium salt, lactofen,tiafenacil, and ethyl[(3-{2-chloro-4-fluoro-5-[3-methyl-4-(trifluoromethyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-1-yl]phenoxy}pyridin-2-yl)oxy]acetate(including agriculturally acceptable salts and derivatives thereof foreach).

In another embodiment, the present invention includes—[7] the herbicidalcomposition according to [1], wherein B-4 is a group consisting ofbicyclopyrone, mesotrione, tembotrione, isoxaflutole, fenquinotrione,topramezone, tolpyralate, lancotrione-sodium salt,2-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide(CAS Registry Number 1400904-50-8),2-chloro-N-(1-methyl-1H-tetrazol-5-yl)-3-(methylthio)-4-(trifluoromethyl)-benzamide(CAS Registry Number 1361139-71-0), and4-(4-fluorophenyl)-6-[(2-hydroxy-6-oxo-1-cyclohexene-1-yl)carbonyl]-2-methyl-1,2,4-triazine-3,5-(2H,4H)-dione(CAS Registry Number 1353870-34-4) (including agriculturally acceptablesalts and derivatives thereof for each).

In another embodiment, the present invention includes—[8] the herbicidalcomposition according to [1], wherein B-5 is a group consisting ofnorflurazon and fluridone (including agriculturally acceptable salts andderivatives thereof for each).

In another embodiment, the present invention includes—[9] the herbicidalcomposition according to [1], wherein B-6 is a group consisting ofbentazone, bromoxynil octanoate, diuron, linuron, fluometuron, simazine,atrazine, ametryn, prometryn, and metribuzin (including agriculturallyacceptable salts and derivatives thereof for each).

In another embodiment, the present invention includes—[10] theherbicidal composition according to [1], wherein B-7 is a groupconsisting of alachlor, acetochlor, metolachlor, S-metolachlor,dimethenamid, dimethenamid-P, pyroxasulfone, and flufenacet (includingagriculturally acceptable salts and derivatives thereof for each).

In another embodiment, the present invention includes—[11] theherbicidal composition according to [1], wherein B-8 is a groupconsisting of trifluralin, pendimethalin, and ethalfluralin (includingagriculturally acceptable salts and derivatives thereof for each).

In another embodiment, the present invention includes—[12] theherbicidal composition according to [1], wherein B-9 is a groupconsisting of 2,4-DB, fluroxypyr, fluroxypyr-meptyl, clopyralid-olaminesalt, clopyralid-potassium salt, clopyralid-triethylammonium salt,halauxifen, halauxifen-methyl, florpyrauxifen, and florpyrauxifen-benzyl(including agriculturally acceptable salts and derivatives thereof foreach).

In another embodiment, the present invention includes—[13] theherbicidal composition according to [1], wherein B-10 is a groupconsisting of a combination of two or more of glyphosate,glyphosate-isopropylammonium salt, glyphosate-ammonium salt,glyphosate-dimethylamine salt, glyphosate-monoethanolamine salt,glyphosate-potassium salt, and glyphosate-guanidine salt (includingagriculturally acceptable salts and derivatives thereof for each).

In another embodiment, the present invention includes—[14] theherbicidal composition according to [1], wherein the B-11 is a groupconsisting of glufosinate, glufosinate-ammonium salt, glufosinate-P, andglufosinate-P-sodium salt (including agriculturally acceptable salts andderivatives thereof for each).

In another embodiment, the present invention includes—[15] theherbicidal composition according to [1], wherein the B-12 is a groupconsisting of EPTC, diflufenzopyr, diflufenzopyr-sodium salt, clomazone,2-[(2,4-dichlorophenyl)methyl]-4,4-dimethylisoxazolidin-3-one (CASRegistry Number: 81777-95-9),(3S,4S)—N-(2-fluorophenyl)-1-methyl-2-oxo-4-[3-(trifluoromethyl)phenyl]-3-pyrrolidinecarboxamide(CAS Registry Number: 2053901-33-8), cinmethylin, MSMA, paraquat,paraquat dichloride, diquat, and diquat dibromide (includingagriculturally acceptable salts and derivatives thereof for each).

In another embodiment, the present invention includes—[16] Theherbicidal composition according to [1], wherein the safener group C isa group consisting of benoxacor, cyprosulfamide, and isoxadifen-ethyl(including agriculturally acceptable salts and derivatives thereof foreach).

The present invention also features—[18] A method for controlling weeds,the method including a step of applying a compound of formula I and atleast one compound selected from the group consisting of the herbicidecompound group B and the safener group C simultaneously or sequentiallyto a place where weeds are growing or to grow.

In one embodiment, the present invention includes—[19] The methodaccording to [18], wherein a compound of formula I and the at least onecompound selected from the group consisting of the herbicide compoundgroup B and the safener group C are used at a weight ratio of 1:0.1 to1:50.

In another embodiment, the present invention includes—[20] The methodaccording to [18] or [19], wherein the place where weeds are growing orto grow is a crop field.

The present invention also features—[21] A use of the herbicidalcomposition according to any one of [1] to [16], for controlling weeds.

Herbicidal compositions according to the present invention also includea compound of formula I and at least one compound selected from thegroup consisting of an herbicide compound group B and a safener group C.

The method for controlling weeds according to the present invention(hereinafter referred to as “present method”) includes the step ofapplying the present composition to a place where weeds are growing orlikely to grow in a crop field, a vegetable field, a land underperennial crops, a non-crop land, or the like. In a crop field and avegetable field, the present composition may be applied before,simultaneously with, and/or after sowing a crop seed.

The present method includes the step of applying a compound of formula Iand at least one compound selected from the group consisting of theherbicide compound group B and the safener group C simultaneously orsequentially to a place where weeds are growing or likely to grow. Inthe case of the sequential application, the order of the application isnot particularly limited.

The present composition is usually a formulation prepared by mixing acompound of formula I and at least one compound selected from the groupconsisting of the herbicide compound group B and the safener group Cwith a carrier such as a solid carrier or a liquid carrier and adding anauxiliary agent for formulation such as a surfactant if necessary.Preferable formulation types of such a formulation are aqueous liquidsuspension concentrates, wettable powders, water dispersible granules,granules, and emulsifiable concentrates. The present composition may beused in combination with a formulation containing another herbicide asan active ingredient.

The total content of a compound of formula I and the at least onecompound selected from the group consisting of the herbicide compoundgroup B and the safener group C in the present composition is within arange of 0.01 to 90% by weight, preferably 1 to 80% by weight.

Hereinafter, when the at least one compound selected from the groupconsisting of the herbicide compound group B is a salt (for example,glyphosate-potassium salt), the weight of the at least one compound isrepresented by the acid equivalent.

A mixing ratio of a compound of formula I to the at least one compoundselected from the group consisting of the herbicide compound group B andthe safener group C in the present composition is within a range of1:0.05 to 1:100, preferably 1:0.1 to 1:50 by weight ratio.

A ratio of application rates of a compound of formula I to the at leastone compound selected from the group consisting of the herbicidecompound group B and the safener group C in the present method is withina range of 1:0.05 to 1:100, preferably 1:0.1 to 1:50 by weight ratio.

In some variations, the mixing ratio of a compound of formula I to theat least one compound selected from the group consisting of theherbicide compound group B and the safener group C in the presentcomposition include about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.5,about 1:0.7, about 1:1, about 1:2, about 1:3, about 1:5, about 1:7,about 1:10, about 1:15, about 1:20, about 1:30, and about 1:50 by weightratio.

In some variations, the ratio of application rates of a compound offormula I to the at least one compound selected from the groupconsisting of the herbicide compound group B and the safener group C inthe present method include about 1:0.1, about 1:0.2, about 1:0.3, about1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:1, about 1:1.2,about 1:1.4, about 1:1.6, about 1:1.8, about 1:2, about 1:2.2, about1:2.4, about 1:2.6, about 1:2.8, about 1:3, about 1:5, about 1:7, about1:10, about 1:15, about 1:20, about 1:30, and about 1:50 by weightratio.

The word “about” in the preceding paragraph means that the specifiedratio includes the ratio in the range increased or decreased by 10% byweight relative to the specified ratio. For example, a ratio of about1:2 includes a range of 1:1.8 to 1:2.2.

In the present composition and the present method, particularlypreferable examples of the combination of a compound of formula I andthe at least one compound selected from the group consisting of theherbicide compound group B and the safener group C and the range ofweight ratio thereof include, but are not limited to, the followingcombinations and the ranges:

-   -   a combination of a compound of formula I and pyrithiobac (1:0.1        to 1:20);    -   a combination of a compound of formula I and pyrithiobac-sodium        salt (1:0.1 to 1:20);    -   a combination of a compound of formula I and chlorimuron-ethyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and foramsulfuron        (1:0.1 to 1:20);    -   a combination of a compound of formula I and halosulfuron-methyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and nicosulfuron (1:0.1        to 1:20);    -   a combination of a compound of formula I and        primisulfuron-methyl (1:0.1 to 1:20);    -   a combination of a compound of formula I and rimsulfuron (1:0.1        to 1:20);    -   a combination of a compound of formula I and        trifloxysulfuron-sodium salt (1:0.1 to 1:20);    -   a combination of a compound of formula I and chlorsulfuron        (1:0.1 to 1:20);    -   a combination of a compound of formula I and        iodosulfuron-methyl-sodium (1:0.1 to 1:20);    -   a combination of a compound of formula I and        iofensulfuron-sodium (1:0.1 to 1:20);    -   a combination of a compound of formula I and metsulfuron-methyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and prosulfuron (1:0.1        to 1:20);    -   a combination of a compound of formula I and        thifensulfuron-methyl (1:0.1 to 1:20);    -   a combination of a compound of formula I and tribenuron-methyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and        thiencarbazone-methyl (1:0.1 to 1:20);    -   a combination of a compound of formula I and cloransulam-methyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and flumetsulam (1:0.1        to 1:20);    -   a combination of a compound of formula I and        imazamethabenz-methyl (1:0.1 to 1:20);    -   a combination of a compound of formula I and imazamox-ammonium        salt (1:0.1 to 1:20);    -   a combination of a compound of formula I and imazapic-ammonium        salt (1:0.1 to 1:20);    -   a combination of a compound of formula I and        imazapyr-isopropylammonium salt (1:0.1 to 1:20);    -   a combination of a compound of formula I and imazaquin-ammonium        salt (1:0.1 to 1:20);    -   a combination of a compound of formula I and        imazethapyr-ammonium salt (1:0.1 to 1:20);    -   a combination of a compound of formula I and fenoxaprop-ethyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and fenoxaprop-P-ethyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and fluazifop-butyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and fluazifop-P-butyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and quizalofop-ethyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and quizalofop-P-ethyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and clethodim (1:0.1 to        1:20);    -   a combination of a compound of formula I and sethoxydim (1:0.1        to 1:20);    -   a combination of a compound of formula I and carfentrazone-ethyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and saflufenacil (1:0.1        to 1:20);    -   a combination of a compound of formula I and sulfentrazone        (1:0.1 to 1:30);    -   a combination of a compound of formula I and pyraflufen-ethyl        (1:0.1 to 1:30);    -   a combination of a compound of formula I and fluthiacet-methyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and flufenpyr-ethyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and flumiclorac-pentyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and flumioxazin (1:0.1        to 1:20);    -   a combination of a compound of formula I and oxyfluorfen (1:0.1        to 1:30);    -   a combination of a compound of formula I and acifluorfen-sodium        salt (1:0.1 to 1:30);    -   a combination of a compound of formula I and fomesafen-sodium        salt (1:0.1 to 1:30);    -   a combination of a compound of formula I and lactofen (1:0.1 to        1:30);    -   a combination of a compound of formula I and tiafenacil (1:0.1        to 1:20);    -   a combination of a compound of formula I and ethyl        [(3-{2-chloro-4-fluoro-5-[3-methyl-4-(trifluoromethyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-1-yl]phenoxy}pyri        din-2-yl)oxy]acetate (1:0.1 to 1:20);    -   a combination of a compound of formula I and bicyclopyrone        (1:0.1 to 1:20);    -   a combination of a compound of formula I and mesotrione (1:0.1        to 1:20);    -   a combination of a compound of formula I and tembotrione (1:0.1        to 1:20);    -   a combination of a compound of formula I and isoxaflutole (1:0.1        to 1:20);    -   a combination of a compound of formula I and fenquinotrione        (1:0.1 to 1:20);    -   a combination of a compound of formula I and topramezone (1:0.1        to 1:20);    -   a combination of a compound of formula I and tolpyralate (1:0.1        to 1:20);    -   a combination of a compound of formula I and lancotrione-sodium        salt (1:0.1 to 1:20);    -   a combination of a compound of formula I and        2-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide        (CAS Registry Number: 1400904-50-8) (1:0.1 to 1:20);    -   a combination of a compound of formula I and        2-chloro-N-(1-methyl-JH-tetrazol-5-yl)-3-(methylthio)-4-(trifluoromethyl)-benzamide        (CAS Registry Number: 1361139-71-0) (1:0.1 to 1:20);    -   a combination of a compound of formula I and        4-(4-fluorophenyl)-6-[(2-hydroxy-6-oxo-1-cyclohexene-1-yl)carbonyl]-2-met-hyl-1,2,4-triazine-3,5(2H,4H)-dione        (CAS Registry Number: 1353870-34-4) (1:0.1 to 1:20);    -   a combination of a compound of formula I and norflurazon (1:0.1        to 1:20);    -   a combination of a compound of formula I and fluridone (1:0.1 to        1:20);    -   a combination of a compound of formula I and bentazone (1:1 to        1:50);    -   a combination of a compound of formula I and bromoxynil        octanoate (1:1 to 1:50);    -   a combination of a compound of formula I and diuron (1:1 to        1:50);    -   a combination of a compound of formula I and linuron (1:1 to        1:50);    -   a combination of a compound of formula I and fluometuron (1:1 to        1:50);    -   a combination of a compound of formula I and simazine (1:1 to        1:50);    -   a combination of a compound of formula I and atrazine (1:1 to        1:50);    -   a combination of a compound of formula I and ametryn (1:1 to        1:50);    -   a combination of a compound of formula I and prometryn (1:1 to        1:50);    -   a combination of a compound of formula I and metribuzin (1:1 to        1:50);    -   a combination of a compound of formula I and alachlor (1:1 to        1:50);    -   a combination of a compound of formula I and acetochlor (1:1 to        1:50);    -   a combination of a compound of formula I and metolachlor (1:1 to        1:50);    -   a combination of a compound of formula I and S-metolachlor (1:1        to 1:50);    -   a combination of a compound of formula I and dimethenamid (1:1        to 1:50);    -   a combination of a compound of formula I and dimethenamid-P (1:1        to 1:50);    -   a combination of a compound of formula I and pyroxasulfone        (1:0.1 to 1:20);    -   a combination of a compound of formula I and flufenacet (1:0.1        to 1:20);    -   a combination of a compound of formula I and trifluralin (1:1 to        1:50);    -   a combination of a compound of formula I and pendimethalin (1:1        to 1:50);    -   a combination of a compound of formula I and ethalfluralin (1:1        to 1:50);    -   a combination of a compound of formula I and 2,4-DB (1:1 to        1:50);    -   a combination of a compound of formula I and fluroxypyr (1:1 to        1:50);    -   a combination of a compound of formula I and fluroxypyr-meptyl        (1:1 to 1:50);    -   a combination of a compound of formula I and clopyralid-olamine        salt (1:1 to 1:50);    -   a combination of a compound of formula I and        clopyralid-potassium salt (1:1 to 1:50);    -   a combination of a compound of formula I and        clopyralid-triethylammonium salt (1:1 to 1:50);    -   a combination of a compound of formula I and halauxifen (1:0.1        to 1:20);    -   a combination of a compound of formula I and halauxifen-methyl        (1:0.1 to 1:20);    -   a combination of a compound of formula I and florpyrauxifen        (1:0.1 to 1:20);    -   a combination of a compound of formula I and        florpyrauxifen-benzyl (1:0.1 to 1:20);    -   a combination of a compound of formula I and glyphosate (1:1 to        1:50);    -   a combination of a compound of formula I and        glyphosate-isopropylammonium salt (1:1 to 1:50);    -   a combination of a compound of formula I and glyphosate-ammonium        salt (1:1 to 1:50);    -   a combination of a compound of formula I and        glyphosate-dimethylamine salt (1:1 to 1:50);    -   a combination of a compound of formula I and        glyphosate-monoethanolamine salt (1:1 to 1:50);    -   a combination of a compound of formula I and        glyphosate-potassium salt (1:1 to 1:50);    -   a combination of a compound of formula I and        glyphosate-guanidine salt (1:1 to 1:50);    -   a combination of a compound of formula I and glufosinate (1:1 to        1:50);    -   a combination of a compound of formula I and        glufosinate-ammonium salt (1:1 to 1:50);    -   a combination of a compound of formula I and glufosinate-P (1:1        to 1:50);    -   a combination of a compound of formula I and        glufosinate-P-sodium salt (1:1 to 1:50);    -   a combination of a compound of formula I and EPTC (1:1 to 1:50);    -   a combination of a compound of formula I and diflufenzopyr (1:1        to 1:50);    -   a combination of a compound of formula I and        diflufenzopyr-sodium salt (1:1 to 1:50);    -   a combination of a compound of formula I and clomazone (1:1 to        1:50);    -   a combination of a compound of formula I and        2-[(2,4-dichlorophenyl)methyl]-4,4-dimethylisoxazolidin-3-one        (CAS Registry Number: 81777-95-9) (1:1 to 1:50);    -   a combination of a compound of formula I and        (3S,4S)-N-(2-fluorophenyl)-1-methyl-2-oxo-4-[3-(trifluoromethyl)phenyl]-3-pyrrolidinecarboxamide        (CAS Registry Number: 2053901-33-8) (1:1 to 1:50);    -   a combination of a compound of formula I and cinmethylin (1:1 to        1:50);    -   a combination of a compound of formula I and MSMA (1:1 to 1:50);    -   a combination of a compound of formula I and paraquat (1:1 to        1:50);    -   a combination of a compound of formula I and paraquat-dichloride        (1:1 to 1:50);    -   a combination of a compound of formula I and diquat (1:1 to        1:50);    -   a combination of a compound of formula I and diquat-dibromide        (1:1 to 1:50);    -   a combination of a compound of formula I and benoxacor (1:0.1 to        1:20);    -   a combination of a compound of formula I and cyprosulfamide        (1:0.1 to 1:20); or    -   a combination of a compound of formula I and isoxadifen-ethyl        (1:0.1 to 1:20).

Before, simultaneously with, and/or after sowing a crop seed treatedwith one or more compounds selected from the group consisting of aninsecticide compound, a nematicide compound, a fungicide compound, andthe like, the present composition may be applied to the field in whichthe crop seed have been sown or is to be sown.

In some embodiments, the present composition may be used in combinationwith another pesticidally-active compound. Examples of the insecticidecompound, the nematicide compound, and the fungicide compound which maybe used in combination with the present composition includeneonicotinoid compounds, diamide compounds, carbamate compounds,organophosphorus compounds, biological nematicide compounds, otherinsecticide compounds and nematicide compounds, azole compounds,strobilurin compounds, metalaxyl compounds, SDHI compounds, and otherfungicide compounds and plant growth regulators.

EXAMPLES

The presently disclosed subject matter will be better understood byreference to the following Examples, which are provided as exemplary ofthe invention, and not by way of limitation.

Compound Synthesis and Characterization

Steps in the following Examples illustrate a procedure for each step inan overall synthetic transformation, and the starting material for eachstep may not have necessarily been prepared by a procedure described inother Examples or Steps. ¹H-NMR spectra are reported in ppm downfieldfrom tetramethylsilane; “s” means singlet, “d” means doublet, “t” meanstriplet, “q” means quartet, “m” means multiplet, “dd” means doublet ofdoublets, “dt” means doublet of triplets, and “br s” means broadsinglet. Mass spectra (MS) are reported as the molecular weight of thehighest isotopic abundance parent ion (M+1) formed by addition of H⁺(molecular weight of 1) to the molecule, or (M−1) formed by the loss ofH⁺ (molecular weight of 1) from the molecule, observed by using liquidchromatography coupled to a mass spectrometer (LCMS) using eitheratmospheric pressure chemical ionization (AP+) where “amu” stands forunified atomic mass units or electrospray ionization (ES⁺).

Example 1. Preparation of2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1) and2,2,7-trifluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 2)

As shown in Step 1 of Scheme 3, to a degassed mixture of1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (3.0 g, 12.0 mmol) inisopropyl acetate (50 mL) was added Pd(OAc)₂ (269 mg, 1.2 mmol),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (Sphos, 985 mg, 2.4mmol) and K₂CO₃ (3.3 g, 24.0 mmol) under an atmosphere of nitrogen. Theresulting mixture was stirred at room temperature for 5 mins, followedby the addition of a solution of pentafluorobenzene (4.0 g, 24.0 mmol)in isopropyl acetate (10 mL). The resulting mixture was stirred at 80°C. for 16 hours under nitrogen, cooled to room temperature, filtered,and concentrated under reduced pressure. The residue was purified byflash column chromatography (0-40% ethyl acetate in petroleum ether) toafford 2,2′,3,4,5,6-hexafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl(Compound 1001, 2.6 g, 64% yield) as a reddish solid: GCMS calculatedfor (C₁₃H₅F₆NO₃), 337.0; found, 337.0.

As shown in Step 2 of Scheme 3, to a stirred mixture of2,2′,3,4,5,6-hexafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl (2.6 g, 7.71mmol) in DCM (50 mL) was added boron tribromide (7.7 g, 30.84 mmol)dropwise at −78° C. under an atmosphere of nitrogen. The mixture wasstirred at −78° C. for 1 hour, then slowly warmed to room temperatureover 16 hours. The reaction was diluted with water and extracted withDCM. The combined organics were washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure toafford 2,2′,3′,4′,5′,6′-hexafluoro-5-nitro-[1,1′-biphenyl]-4-ol(Compound 1002, 2.4 g, crude) as a yellow solid: MS (ESI) calculated for(C₁₂H₃F₆NO₃) [M−1], 322.0; found, 322.1. This material was used insubsequent steps without further purification.

As shown in Step 3 of Scheme 3, to a stirred solution of2,2′,3′,4′,5′,6′-hexafluoro-5-nitro-[1,1′-biphenyl]-4-ol (2.4 g, 7.42mmol) in EtOH (20 mL) was added a solution of sodium hyposulfite (6.4 g,37.1 mmol) in water (20 mL). The resulting mixture was refluxed for 1hour, cooled to room temperature, concentrated under reduced pressure,diluted with water, and extracted with ethyl acetate. The combinedorganics were washed with brine, dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to afford5-amino-2,2′,3′,4′,5′,6′-hexafluoro-[1,1′-biphenyl]-4-ol (Compound 1003,2.0 g, crude) as a yellow solid: MS (ESI) calculated for (C₁₂H₅F₆NO)[M−1], 292.1; found, 292.1. This material was used in subsequent stepswithout further purification.

As shown in Step 4 of Scheme 3, to a solution of5-amino-2,2′,3′,4′,5′,6′-hexafluoro-[1,1′-biphenyl]-4-ol (1.0 g, 3.41mmol) in EtOAc (10 mL) were added ethyl 2-bromo-2,2-difluoroacetate (690mg, 3.41 mmol) and triethylamine (345 mg, 3.41 mmol). The mixture wasstirred at 70° C. for 1 hour, cooled to room temperature, diluted withwater, and extracted with EtOAc. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered, concentratedunder reduced pressure, and purified by flash chromatography (0-50%ethyl acetate in petroleum ether) to afford2-bromo-2,2-difluoro-N-(2′,3′,4′,5′,6,6′-hexafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide(Compound 1004, 800 mg, 52% yield) as a yellow solid: MS (ESI)calculated for (C₁₄H₄BrF₈NO₂) [M+1]⁺, 450.1; found, 450.1.

As shown in Step 5 of Scheme 3, to a stirred solution of2-bromo-2,2-difluoro-N-(2′,3′,4′,5′,6,6′-hexafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide(600 mg, 1.33 mmol) in DMF (6 mL) was added K₂CO₃ (276 mg, 2.00 mmol).The mixture was stirred at 50° C. for 16 hours, diluted with water, andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered, concentratedunder reduced pressure, and purified by flash chromatography (0-20%ethyl acetate in petroleum ether) to afford2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1, 320 mg, 64% yield) as a yellow solid: MS (ESI) calculatedfor (C₁₄H₃F₈NO₂) [M−1]⁻, 368.1; found, 368.1.

As shown in Step 6 of Scheme 3, to a solution of2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(200 mg, 0.54 mmol) in DMF (2 mL) were added K₂CO₃ (74 mg, 0.54 mmol)and 3-bromoprop-1-yne (70 mg, 0.54 mmol). The mixture was stirred atroom temperature for 16 hours, diluted with water, and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered, concentrated under reducedpressure, and purified by flash chromatography (0-30% ethyl acetate inpetroleum ether) to afford2,2,7-trifluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 2, 120 mg, 54% yield) as an off-white solid: GCMS calculatedfor (C₁₇H₅F₈NO₂), 407.0; found, 407.0; ¹H-NMR (400 MHz, DMSO-d₆) δ7.81-7.67 (m, 2H), 4.88 (s, 2H), 3.45 (s, 1H); ¹⁹F-NMR (400 MHz,DMSO-d₆) δ −74.85, −115.56, −140.50, −153.03, −162.01.

The following compounds were produced by procedures analogous to that ofStep 6 of Scheme 3 by reacting Compound 1 with the appropriate alkylhalide or alkyl triflate:

-   -   2,2,7-trifluoro-4-methyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one        (Compound 5, 24 mg, 23% yield) as a white solid: GCMS calculated        for (C₁₅H₅F₈NO₂), 383.0, found, 383.0; ¹H-NMR (400 MHz, DMSO-d₆)        δ 7.87-7.62 (m, 2H), 3.43 (s, 3H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ        −74.05, −116.55, −140.32, −153.34, −162.15;    -   4-benzyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one        (Compound 10, 26.3 mg, 30% yield) as a white solid: GCMS        calculated for (C₂₁H₉F₈NO₂), 459.1; found, 459.0; ¹H-NMR (400        MHz, methanol-d₄) δ 7.42-7.37 (m, 4H), 7.35-7.31 (m, 3H), 5.33        (s, 2H); ¹⁹F-NMR (376 MHz, methanol-d₄) δ −78.80, −116.83,        −142.52, −155.24-164.83;    -   4-allyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one        (Compound 11, 29.6 mg, 44% yield) as a white solid. GCMS        calculated for (C₁₇H₇F₈NO₂), 409.0; found, 409.0; ¹H-NMR (400        MHz, DMSO-d₆) δ 7.79-7.74 (m, 1H), 7.62 (d, J=6.4 Hz, 1H), 5.88        (m, 1H), 5.27-5.14 (m, 2H), 4.68-4.62 (m, 2H); ¹⁹F-NMR (376 MHz,        DMSO-d₆) δ −74.67, −116.18, −140.50, −153.27, −162.03;    -   4-ethyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one        (Compound 12, 28.0 mg, 43% yield) as a white solid: GCMS        calculated for (C₁₆H₇F₈NO₂), 397.0; found, 397.0; ¹H-NMR (400        MHz, DMSO-d₆) δ 7.80 (d, J=6.4 Hz, 1H), 7.78-7.72 (m, 1H), 4.05        (m, 2H), 1.19 (t, J=7.2 Hz, 3H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ        −74.60, −116.48, −140.36, −153.44, −162.15;    -   2,2,7-trifluoro-6-(perfluorophenyl)-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one        (Compound 13, 25 mg, 32% yield) as a white solid: GCMS        calculated for (C₁₇H₉F₈NO₂), 411.1; found, 411.0; ¹H-NMR (400        MHz, DMSO-d₆) δ 7.82-7.72 (m, 2H), 3.98 (t, J=7.2 Hz, 2H),        1.65-1.59 (m, 2H), 0.91 (t, J=6.8 Hz, 3H); ¹⁹F-NMR (400 MHz,        DMSO-d₆) δ −74.70, −116.40, −140.10, −153.46, −162.12;    -   4-(3-cyclopropylprop-2-yn-1-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one        (Compound 14, 28 mg, 33% yield) as a white solid: GCMS        calculated for (C₂₀H₉F₈NO₂), 447.1; found, 447.1; ¹H-NMR (400        MHz, DMSO-d₆) δ 7.76 (d, J=9.6 Hz, 1H), 7.71 (d, J=6.4 Hz, 1H),        4.80 (s, 2H), 1.32-1.24 (m, 1H), 0.80-0.69 (m, 2H), 0.58-0.50        (m, 2H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −74.72, −115.70, −140.77,        −153.12, −162.06;    -   4-(but-2-yn-1-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one        (Compound 18, 31.0 mg, 37% yield) as a white solid: GCMS        calculated for (C₁₈H₇F₈NO₂), 421.0; found, 421.1; ¹H-NMR (400        MHz, DMSO-d₆) δ 7.78-7.73 (m, 2H), 4.83-4.78 (m, 2H), 1.78 (s,        3H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −74.68, −115.65, −140.58,        −153.09, −161.96;    -   2,2,7-trifluoro-4-(2-methylallyl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one        (Compound 19, 250 mg, 72% yield) as a white solid: GCMS        calculated for (C₁₈H₉F₈NO₂), 423.0; found, 423.0. ¹H-NMR (400        MHz, DMSO-d₆) δ 7.77 (d, J=9.6 Hz, 1H), 7.53 (d, J=6.4 Hz, 1H),        4.92-4.88 (m, 1H), 4.72-4.66 (m, 1H), 4.56 (s, 2H), 1.75 (d,        J=1.2 Hz, 3H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −75.05, −116.00,        −140.57, −153.23, −162.01;    -   2,2,7-trifluoro-6-(perfluorophenyl)-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one        (Compound 20, 58 mg, 39% yield) as a white solid: GCMS        calculated for (C₁₆H₄F₁₁NO₂), 451.0; found, 451.0; ¹H-NMR (400        MHz, DMSO-d₆) δ 7.97 (d, J=6.4 Hz, 1H), 7.80 (d, J=9.2 Hz, 1H),        5.08-4.97 (m, 2H); ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −67.95, −75.15,        −115.30, −140.49, −152.81, −161.86;    -   2,2,7-trifluoro-4-(2-fluorobenzyl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one        (Compound 23, 89 mg, 66% yield) as a white solid: MS (ESI)        calculated for (C₂₁H₈F₉NO₂) [M+1]⁺, 478.2; found, 477.9; ¹H-NMR        (400 MHz, DMSO-d6) δ 7.78 (d, J=9.6 Hz, 1H), 7.65 (d, J=6.4 Hz,        1H), 7.43-7.33 (m, 1H), 7.33-7.21 (m, 2H), 7.18-7.16 (m, 1H),        5.32 (s, 2H); ¹⁹F-NMR (400 MHz, DMSO-d6) δ −74.91, −115.69,        −117.44, −140.68, −153.15, −162.02;    -   2,2,7-trifluoro-4-isopropyl-6-(perfluorophenyl)-2H-benzo[b][1,4]        oxazin-3(4H)-one (Compound 24, 34.1 mg, 15% yield) as a light        yellow solid: GCMS calculated for (C₁₇H₉F₈NO₂), 411.0; found,        411.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.72-7.62 (m, 2H), 5.41-5.30        (m, 1H), 1.39 (d, J=6.4 Hz, 6H); ¹⁹F-NMR (400 MHz, DMSO-d6) δ        −67.27, −112.83, −140.84, −153.73, −162.21.

Example 2. Preparation of7-fluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound3) and7-fluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 4)

As shown in Step 1 of Scheme 4, to a solution of5-amino-2,2′,3′,4′,5′,6′-hexafluoro-[1,1′-biphenyl]-4-ol (500 mg, 1.70mmol) in dimethoxyethane (DME, 2.5 mL) and H₂O (2.5 mL) at 0° C. underan atmosphere of nitrogen was added NaHCO₃ (429 mg, 5.11 mmol) andchloroacetyl chloride (288 mg, 2.55 mmol). The mixture was stirred at15° C. for 30 minutes, then heated to 80° C. for 12 hours. Aftercooling, the suspension was filtered and the collected solid was washedwith water and dried under vacuum to afford7-fluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound3, 350 mg, 60% yield) as a brown solid: MS (ESI) calculated forC₁₄H₅FNO₂ [M−H]⁻=332.0, found, 332.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 10.93(s, 1H), 7.18 (d, J=10.4 Hz, 1H), 6.96 (d, J=7.2 Hz, 1H), 4.71 (s, 2H);¹⁹F-NMR (400 MHz, DMSO-d6) δ −119.20, −141.34, −154.32, −162.26.

As shown in Step 2 of Scheme 4, to a solution of7-fluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (60 mg,0.18 mmol) in DMF (1 mL) were added K₂CO₃ (27 mg, 0.19 mmol) and3-bromoprop-1-yne (23 mg, 0.19 mmol) at room temperature under nitrogen.The mixture was stirred at room temperature for 8 hours, diluted withwater, and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filtered,concentrated under reduced pressure, and purified by preparativereversed-phase HPLC using the following conditions—Column: XBridge PrepOBD C18 Column, 30×150 mm 5 um; Mobile Phase A: Water (10 mM NH₄HCO₃),Mobile Phase B: acetonitrile; Gradient: 45 B to 75 B, to afford7-fluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 4, 23 mg, 20% yield) as a white solid: GCMS calculated for(C₁₇H₇F₆NO), 371.0, found, 371.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.43 (d,J=6.8 Hz, 1H), 7.28 (d, J=9.6 Hz, 1H), 4.86 (s, 2H), 4.75 (s, 2H), 3.30(s, 1H); ¹⁹F NMR (400 MHz, DMSO-d₆) δ −118.25, −140.71, −153.89,−162.21.

Example 3. Preparation of7-fluoro-2,2-dimethyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 6) and7-fluoro-2,2-dimethyl-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 7)

As shown in Step 1 of Scheme 5, to a solution of2,2′,3′,4′,5′,6′-hexafluoro-5-nitro-[1,1′-biphenyl]-4-ol (500 mg, 1.54mmol) in acetonitrile (5 mL) were added ethyl 2-bromo-2-methylpropanoate(362 mg, 1.85 mmol) and K₂CO₃ (427 mg, 3.09 mmol). The resultingsolution was stirred at 80° C. for 2 hours before concentration underreduced pressure. The residue was purified by reversed-phase flashchromatography (5-35% acetonitrile in water) to afford ethyl2-([2,2′,3′,4′,5′,6′-hexafluoro-5-nitro-[1,1′-biphenyl]-4-yl]oxy)-2-methylpropanoate(Compound 1005, 390 mg, 52% yield) as a yellow solid: ¹H-NMR (400 MHz,DMSO-d₆) δ 8.34 (d, J=8.4 Hz, 1H), 7.18 (d, J=6.8 Hz, 1H), 4.20 (m, 2H),1.62 (s, 6H), 1.19 (t, J=7.2 Hz, 3H).

As shown in Step 2 of Scheme 5, to a solution of ethyl2-([2,2′,3′,4′,5′,6′-hexafluoro-5-nitro-[1,1′-biphenyl]-4-yl]oxy)-2-methylpropanoate(100 mg, 0.22 mmol) in acetic acid (1 mL) was added iron powder (63 mg,1.14 mmol). The resulting mixture was stirred at 60° C. for 16 hours,cooled to room temperature, filtered, and concentrated under reducedpressure. The residue was purified by reversed-phase flashchromatography (20-70% acetonitrile in water) to afford7-fluoro-2,2-dimethyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 6, 35 mg, 40% yield) as a white solid: MS (ESI) calculated forC₁₆H₉F₆NO₂ [M−H]⁻, 360.1; found, 360.0; ¹H-NMR (400 MHz, DMSO-d₆) δ10.88 (s, 1H), 7.16 (d, J=10.4 Hz, 1H), 6.97 (d, J=6.8 Hz, 1H), 1.47 (s,6H); ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −118.85, −141.24, −154.31, −162.25.

As shown in Step 3 of Scheme 5, to a solution of7-fluoro-2,2-dimethyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(100 mg, 0.27 mmol) in DMF (2 mL) were added K₂CO₃ (42 mg, 0.31 mmol)and propargyl bromide (36 mg, 0.31 mmol). The mixture was stirred atroom temperature for 2 hours, diluted with water, and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered, concentrated under reducedpressure, and purified by reversed-phase flash chromatography (5%-40%acetonitrile in water) to afford7-fluoro-2,2-dimethyl-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 7, 35 mg, 30% yield) as a white solid: GCMS calculated for(C₁₉H₁₁F₆NO₂), 399.0; found, 399.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.43 (d,J=6.4 Hz, 1H), 7.25 (d, J=10.4 Hz, 1H), 4.75 (s, 2H), 3.30 (s, 1H), 1.49(s, 6H); ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −117.89, −140.62, −153.97,−162.25.

Example 4. Preparation of7-fluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)spiro[benzo[b][1,4]oxazine-2,1′-cyclopropan]-3(4H)-one(Compound 9)

As shown in Step 1 of Scheme 6, to a solution of1-bromo-2,4-difluoro-5-nitrobenzene (102 mg, 4.30 mmol) in THF (5 mL) at0° C. was added NaH (60% oil dispersion, 206 mg, 5.16 mmol) in portionsunder an atmosphere in nitrogen. The mixture was stirred at roomtemperature for 10 minutes, followed by the addition of 15-crown-5 (94mg, 0.43 mmol) and methyl 1-hydroxycyclopropane-1-carboxylate (500 mg,4.30 mmol). The mixture was stirred at room temperature for 16 hours,cooled to 0° C., and diluted with water at 0° C., and extracted withethyl acetate (3×15 mL). The combined organics were washed with brine,dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by flash columnchromatography (0-35% ethyl acetate in petroleum ether) to afford methyl1-(4-bromo-5-fluoro-2-nitrophenoxy)cyclopropane-1-carboxylate (Compound1006, 500 mg, 33% yield) as a yellow solid: GCMS calculated forC₁₁H₉BrFNO₅, 332.9; found, 332.9.

As shown in Step 2 of Scheme 6, to a solution of1,2,3,4,5-pentafluorobenzene (503 mg, 2.99 mmol) in isopropyl acetate (5mL) under an atmosphere of nitrogen were added K₂CO₃ (413 mg, 2.99mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos, 122 mg,0.29 mmol) and Pd(OAc)₂ (33 mg, 0.15 mmol). The mixture was stirred atroom temperature for 5 minutes, followed by the addition of methyl1-(4-bromo-5-fluoro-2-nitrophenoxy)cyclopropane-1-carboxylate (500 mg,1.49 mmol). The mixture was stirred at 80° C. for 12 hours under anatmosphere of nitrogen, cooled to room temperature, diluted with water,and extracted with ethyl acetate (3×10 mL). The combined organics werewashed with brine, dried over anhydrous sodium sulfate, filtered,concentrated under reduced pressure, and purified by flashchromatography (0-20% ethyl acetate in petroleum ether) to afford methyl1-((2,2′,3′,4′,5′,6′-hexafluoro-5-nitro-[1,1′-biphenyl]-4-yl)oxy)cyclopropane-1-carboxylate(Compound 1007, 400 mg, 71% yield) as a brown oil: GCMS calculated forC₁₇H₉F₆NO₅=421.0, found, 421.0.

As shown in Step 3 of Scheme 6, to a solution of methyl1-((2,2′,3′,4′,5′,6′-hexafluoro-5-nitro-[1,1′-biphenyl]-4-yl)oxy)cyclopropane-1-carboxylate(200 mg, 0.47 mmol) in acetic acid (1 mL) was added iron powder (132 mg,2.37 mmol). The mixture was stirred at 60° C. for 12 hours. Thesuspension was cooled to room temperature, filtered, and the filtrateconcentrated under reduced pressure. The residue was purified bypreparative reversed-phase HPLC using the following conditions—WatersXBridge C18 column (30 mm×150 mm, 5 um, 130 angstrom); mobile phase A:water (10 mM NH₄HCO₃); mobile phase B: acetonitrile; gradient: 55% to66% B/A, to afford7-fluoro-6-(2,3,4,5,6-pentafluorophenyl)-4H-spiro[1,4-benzoxazine-2,1′-cyclopropan]-3-one(Compound 8, 100 mg, 58% yield) as a white solid: MS (ESI) calculatedfor C₁₆H₇F₆NO₂) [M−1]⁻, 358.0; found, 358.0; ¹H-NMR (400 MHz, DMSO-d₆) δ11.02 (s, 1H), 7.12 (d, J=10.4 Hz, 1H), 6.99 (d, J=6.8 Hz, 1H),1.35-1.29 (m, 2H), 1.29-1.23 (m, 2H); ¹⁹F-NMR (400 MHz, DMSO-d₆) δ−118.92, −141.27, −154.15, −162.24.

As shown in Step 4 of Scheme 6, to a solution of7-fluoro-6-(2,3,4,5,6-pentafluorophenyl)-4H-spiro[1,4-benzoxazine-2,1′-cyclopropan]-3-one(50 mg, 0.13 mmol) in DMF (1 mL) were added K₂CO₃ (21 mg, 0.15 mmol) andpropargyl bromide (18 mg, 0.15 mmol). The mixture was stirred at roomtemperature for 2 hours, filtered, and the filtrate purified bypreparative reversed-phase HPLC using the following conditions—WatersSunFire C18 column (30 mm×150 mm, 5 um); mobile phase A: water (0.1%TFA); mobile phase B: acetonitrile; gradient: 50% B/A to 90% B/A, toafford7-fluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)spiro[benzo[b][1,4]oxazine-2,1′-cyclopropan]-3(4H)-one(Compound 9, 21 mg, 37% yield) as a white solid: GCMS calculated forC₁₉H₉F₆NO₂, 397.0; found, 397.0; ¹H-NMR (400 MHz, methanol-d₄) δ 7.37(d, J=6.4 Hz, 1H), 6.99 (d, J=9.6 Hz, 1H), 4.78 (d, J=2.4 Hz, 2H), 2.76(t, J=2.4 Hz, 1H), 1.48-1.39 (m, 2H), 1.38-1.32 (m, 2H); ¹⁹F-NMR (400MHz, DMSO-d6) δ−119.24, −142.60, −157.13, −165.16.

Example 5. Preparation of2,2-difluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 15) and2,2-difluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 16)

As shown in Step 1 of Scheme 7, to a degassed mixture of4-bromo-1-methoxy-2-nitrobenzene (2.0 g, 8.62 mmol) in isopropyl acetate(10 mL) were added Pd(OAc)₂ (190 mg, 0.86 mmol), Sphos (700 mg, 1.72mmol), and K₂CO₃ (2.4 g, 17.2 mmol) under a nitrogen atmosphere. Themixture was stirred at room temperature for 5 minutes and a solution ofpentafluorobenzene (2.9 g, 17.24 mmol) in isopropyl acetate (10 mL) wasadded. The resulting mixture was stirred at 80° C. for 16 hours undernitrogen, cooled to room temperature, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography(0%-45% ethyl acetate in petroleum ether) to afford2,3,4,5,6-pentafluoro-4′-methoxy-3′-nitro-1,1′-biphenyl (Compound 1008,1.7 g, 54% yield) as a brown solid: GCMS calculated for (C₁₃H₆F₅NO₃),319.0; found, 319.0.

As shown in Step 2 of Scheme 7, to a stirred solution of2,3,4,5,6-pentafluoro-4-methoxy-3-nitro-1,1-biphenyl (1.3 g, 4.1 mmol)in DCM (10 mL) was added boron tribromide (5.1 g, 20.4 mmol) dropwise at−78° C. under a nitrogen atmosphere. The resulting mixture was stirredat −78° C. for 2 hours, then warmed to room temperature and stirred foran additional 16 hours. The reaction diluted with water, extracted withDCM, and the combined organics washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure toafford 2′,3′,4′,5′,6′-pentafluoro-3-nitro-[1,1′-biphenyl]-4-ol (Compound1009, 1.2 g, crude) as a yellow solid: MS (ESI) calculated for(C₁₂H₄F₅NO₃) [M−1]⁻, 304.0; found, 303.8. This material was used insubsequent reactions as is.

As shown in Step 3 of Scheme 7, to a stirred solution of2′,3′,4′,5′,6′-pentafluoro-3-nitro-[1,1′-biphenyl]-4-ol (1.3 g, 4.2mmol) in EtOH (6 mL) was added a solution of sodium hyposulfite (3.6 g,20.8 mmol) in water (6 mL). The mixture was stirred at reflux for 1hour, cooled to room temperature, and the volatiles removed underreduced pressure. The resulting mixture was diluted with water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to afford3-amino-2′,3′,4′,5′,6′-pentafluoro-[1,1′-biphenyl]-4-ol (Compound 1010,400 mg, crude) as a yellow solid: MS (ESI) calculated for (C₁₂H₆F₅NO)[M−1]⁻, 274.0; found, 274.1. This material was used in subsequentreactions as is.

As shown in Step 4 of Scheme 7, to a solution of3-amino-2′,3′,4′,5′,6′-pentafluoro-[1,1′-biphenyl]-4-ol (169 mg, 0.61mmol) in ethyl acetate (2 mL) were added ethyl2-bromo-2,2-difluoroacetate (140 mg, 0.69 mmol) and TEA (70 mg, 0.69mmol). The mixture was stirred at 50° C. for 2 hours, cooled to roomtemperature, diluted with water, and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure toafford2-bromo-2,2-difluoro-N-(2′,3′,4′,5′,6′-pentafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide (Compound 1011, 350 mg, crude) as a brown oil: MS (ESI)calculated for (C₁₄H₅BrF₇NO₂) [M−1]⁻, 429.9; found, 431.9. This materialwas used in subsequent reactions as is.

As shown in Step 5 of Scheme 7, to a stirred solution of2-bromo-2,2-difluoro-N-(2′,3′,4′,5′,6′-pentafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide(268 mg, 0.62 mmol) in DMF (3 mL) was added K₂CO₃ (129 mg, 0.93 mmol).The mixture was stirred at 50° C. for 16 hours, cooled to roomtemperature, diluted with water, and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure, andpurified by flash chromatography (0%-30% ethyl acetate in petroleumether) to afford2,2-difluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 15, 25 mg, 12% yield) as a white solid: MS (ESI) calculatedfor (C₁₄H₄F₇NO₂) [M−1]⁻, 350.0; found, 350.0; ¹H-NMR (400 MHz, DMSO-d₆)δ 12.15 (b, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.33-7.23 (m, 1H), 7.21 (d,J=2.0 Hz, 1H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −75.08, −143.46, −155.67,−162.52.

As shown in Step 6 of Scheme 7, to a stirred solution of2,2-difluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (78mg, 0.22 mmol) in DMF (1 mL) were added 3-bromoprop-1-yne (29 mg, 0.24mmol) and K₂CO₃ (37 mg, 0.27 mmol). The mixture was stirred at roomtemperature for 16 hours, diluted with water, and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered, concentrated under reduced pressure,and purified by reversed-phase flash chromatography (5%-60% acetonitrilein water) to afford2,2-difluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 16, 30 mg, 35% yield) as a white solid: ¹H-NMR (400 MHz,methanol-d₄) δ 7.67-7.57 (m, 1H), 7.48-7.44 (m, 1H), 7.42-7.36 (m, 1H),4.92 (d, J=2.4 Hz, 2H), 2.91-2.81 (m, 1H); ¹⁹F-NMR (376 MHz,methanol-d₄) δ −78.89, −145.03, −157.96, −165.12.

Example 6. Preparation of6-(2,3,4,5,6-pentafluorophenyl)-2,4-dihydro-1,4-benzoxazin-3-one(Compound 21) and6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 22)

As shown in Step 1 of Scheme 8, to a stirred solution of3-amino-2′,3′,4′,5′,6′-pentafluoro-[1,1′-biphenyl]-4-ol (5.0 g, 18.2mmol) and NaHCO₃ (4.5 g, 54.5 mmol) in DME (25 mL) and H₂O (25 mL) wasadded chloroacetyl chloride (3.1 g, 27.25 mmol) dropwise at 0° C. undera nitrogen atmosphere. The mixture was stirred for 16 hours at roomtemperature under a nitrogen atmosphere, diluted with water, andextracted with ethyl acetate. The combined organic layers were washedwith brine, drive over anhydrous sodium sulfate, concentrated underreduced pressure, and purified by flash chromatography (10%-60% ethylacetate in petroleum ether) to afford6-(2,3,4,5,6-pentafluorophenyl)-2,4-dihydro-1,4-benzoxazin-3-one(Compound 21, 3.4 g, 57% yield) as a brown solid: MS (ESI) calculatedfor (C₁₄H₆F₅NO₂) [M−1]⁻, 315.2; found, 314.0; ¹H-NMR (400 MHz, DMSO-d₆)δ 10.89 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 7.00(s, 1H), 4.67 (s, 2H); ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −143.63, −156.62,−162.75.

As shown in Step 2 of Scheme 8, to a stirred solution of6-(2,3,4,5,6-pentafluorophenyl)-2,4-dihydro-1,4-benzoxazin-3-one (100mg, 0.32 mmol) in DMF (1 mL) were added Cs₂CO₃ (124 mg, 0.38 mmol) andpropargyl bromide (45 mg, 0.38 mmol). The resulting mixture was stirredat room temperature for 16 hours, then purified by preparative-HPLCusing the following conditions—Column: X Bridge Shield RP18 OBD Column,19 mm×250 mm, 10 μm; Mobile Phase A: water (10 mM NH₄HCO₃), Mobile PhaseB: acetonitrile; Gradient: 75% B/A to 80% B/A, then 80% B/A to afford6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 22, 39 mg, 34%) as a white solid: MS (ESI) calculated for(C₁₇H₈F₅NO₂) [M+1]⁺, 354.0; found, 354.1; ¹H-NMR (400 MHz, DMSO-d₆) δ7.42 (s, 1H), 7.22 (d, J=7.2 Hz, 2H), 4.93-4.70 (m, 4H), 3.30 (d, J=6.4Hz, 1H); ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −143.06, −156.10, −162.69.

Example 7. Preparation of2,2,7-trifluoro-6-(perfluorophenyl)-4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 17)

As shown in Scheme 9, to a stirred solution of2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(300 mg, 0.81 mmol) and phenylboronic acid (594 mg, 4.87 mmol) in THF (3mL) were added 2-[bis(2-hydroxyethyl)amino]ethanol (986 mg, 9.75 mmol)and copper (II) acetate (118 mg, 0.65 mmol) under nitrogen. The mixturewas stirred at 60° C. for 16 hours, cooled to room temperature, dilutedwith water, and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered, concentrated under reduced pressure, and purified byreversed-phase flash chromatography (30%-80% acetonitrile in water),then further purified by preparative reversed-phase HPLC using thefollowing conditions—Column: X Bridge Shield RP18 OBD Column, 30×150 mm,5 m; Mobile Phase A: Water (10 mM NH₄HCO₃); Mobile Phase B:acetonitrile; Gradient: 51% B/A to 73% B/A, then 73% B/A, to afford2,2,7-trifluoro-6-(perfluorophenyl)-4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 17, 23 mg, 35%) as a white solid: GCMS calculated for(C₂₀H₇F₈NO₂), 445.0; found, 445.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.87-7.80(m, 1H), 7.70-7.58 (m, 3H), 7.56-7.47 (m, 2H), 6.63 (d, J=6.4 Hz, 1H);¹⁹F-NMR (376 MHz, DMSO-d₆) δ −73.83, −116.15, −141.22, −153.75, −162.19.

Example 8. Preparation of7-fluoro-2-methyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 25),(R)-7-fluoro-2-methyl-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 26), and(S)-7-fluoro-2-methyl-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 27)

As shown in Step 1 of Scheme 10, to a stirred mixture of5-amino-2,2′,3′,4′,5′,6′-hexafluoro-[1,1′-biphenyl]-4-ol (100 mg, 0.34mmol) and NaHCO₃ (86 mg, 1.02 mmol) in DME (1.5 mL) and water (1.5 mL)was added 2-chloropropanoyl chloride (65 mg, 0.51 mmol) at 0° C. under anitrogen atmosphere. The mixture was stirred at room temperature for 16hours under a nitrogen atmosphere then concentrated under reducedpressure. The residue was dissolved in DMF (3 mL), K₂CO₃ (94 mg, 0.68mmol) was added, and the resulting mixture stirred at 80° C. for 16hours. After cooling to room temperature, the mixture was diluted withwater and extracted with ethyl acetate. The combined organic layers werewashed with water, dried over anhydrous sodium sulfate, concentratedunder reduced pressure, and purified by reversed-phase flashchromatography (10%-60% acetonitrile in water) to afford7-fluoro-2-methyl-6-(perfluorophenyl)-2H-benzo[h][1,4]oxazin-3(4H)-one(Compound 25, 38 mg, 32% yield) as a white solid: MS (ESI) calculatedfor (C₁₄H₃F₈NO₂) [M−1], 346.2; found, 346.2; ¹H-NMR (400 MHz, DMSO-d₆) δ10.87 (s, 1H), 7.18 (d, J=10.4 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H),4.89-4.80 (m, 1H), 1.51-1.45 (m, 3H).

As shown in Step 2 of Scheme 10, to a stirred mixture of7-fluoro-2-methyl-6-(perfluorophenyl)-2H-benzo[b][1,4] oxazin-3(4H)-one(390 mg, 1.12 mmol), K₂CO₃ (310 mg 2.25 mmol) in DMF (4 mL) was addedpropargyl bromide (401 mg, 3.37 mmol). The resulting mixture was stirredat 80° C. for 4 hours, cooled to room temperature, diluted with water,and extracted with ethyl acetate. The combined organics were washed withwater, dried over anhydrous sodium sulfate, concentrated under reducedpressure, and purified by flash chromatography (0%-30% ethyl acetate inpetroleum ether) to afford racemic7-fluoro-2-methyl-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (300 mg, 69% yield) as a brown-yellow oil.

As shown in Step 3 of Scheme 10, racemic7-fluoro-2-methyl-6-(2,3,4,5,6-pentafluorophenyl)-4-(prop-2-yn-1-yl)-2H-1,4-benzoxazin-3-one(150 mg) was resolved by Chiral Prep-HPLC using the followingconditions—Column: CHIRALPAK AD-H, 2×25 cm, 5 m; Mobile Phase A: Hexane,Mobile Phase B: 1:1 MeOH/EtOH; Gradient: 5% B/A to 5% B/A, to afford(R)-7-fluoro-2-methyl-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 26, 26 mg, 18% yield) as a white solid: MS (EST) calculatedfor (C₁₈H₉F₆NO₂) [M+1]⁺, 386.1; found, 386.1; ¹H-NMR (400 MHz, DMSO-d₆)δ 7.44 (d, J=6.8 Hz, 1H), 7.27 (d, J=10.0 Hz, 1H), 4.96 (q, J=6.8 Hz,1H), 4.77-4.72 (m, 2H), 3.28 (s, 1H), 1.51 (d, J=6.8 Hz, 3H); ¹⁹F-NMR(377 MHz, DMSO-d₆) δ −118.05, −140.67, −154.00, −162.27. Also recoveredwith a longer retention time was(S)-7-fluoro-2-methyl-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 27, 35 mg, 23% yield) as a white solid: MS (ESI) calculatedfor (C₁₈H₉F₆NO₂) [M+1]⁺, 386.1; found, 386.1; ¹H-NMR (400 MHz, DMSO-d₆)δ 7.43 (d, J=6.8 Hz, 1H), 7.28 (d, J=10.0 Hz, 1H), 4.96 (q, J=6.8 Hz,1H), 4.75 (s, 2H), 3.28 (s, 1H), 1.50 (d, J=6.8 Hz, 3H); ¹⁹F-NMR (377MHz, DMSO-d₆) δ −118.04, −140.67, −153.97, −162.25.

Example 9. Preparation of(S)-4-(but-3-yn-2-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 28) and(R)-4-(but-3-yn-2-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 29)

As shown in Step 1 of Scheme 11, to a stirred solution of(R)-but-3-yn-2-ol (200 mg, 2.86 mmol),2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(703 mg, 1.90 mmol) and PPh₃ (749 mg, 2.86 mmol) in THF (5 mL) was addeddiisopropyl azodicarboxylate (DIAD, 578 mg, 2.86 mmol) dropwise at 0° C.under a nitrogen atmosphere. The mixture was stirred at room temperaturefor 2 hours under nitrogen atmosphere, diluted with water, and extractedwith ethyl acetate. The combined organic layers were washed with water,dried over anhydrous sodium sulfate, concentrated under vacuum, andpurified by preparative-TLC (1:10 EtOAc/Petroleum ether) to afford(S)-4-(but-3-yn-2-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 28, 73 mg, 9% yield) as a white solid: GCMS calculated for(C₁₈H₇F₈NO₂), 421.0; found, 421.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.96 (d,J=6.4 Hz, 1H), 7.84-7.74 (m, 1H), 5.98-5.86 (m, 1H), 3.68 (d, J=2.4 Hz,1H), 1.64 (d, J=7.2 Hz, 3H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −74.63,−77.16, −115.34, −140.69, −153.45, −162.12.

Similarly, as shown in Step 2 of Scheme 11, the same procedure asdescribed for Step 1 was employed, using (S)-but-3-yn-2-ol instead of(R)-but-3-yn-2-ol, to produce(R)-4-(but-3-yn-2-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 29, 49 mg, 21% yield) as a white solid: GCMS calculated for(C₁₈H₇F₈NO₂), 421.0; found, 421.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.96 (d,J=6.4 Hz, 1H), 7.80 (d, J=9.6 Hz, 1H), 5.97-5.87 (m, 1H), 3.69 (d, J=2.4Hz, 1H), 1.64 (d, J=7.2 Hz, 3H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −74.75,−77.34, −115.34, −140.91, −153.37, −162.17.

Example 10. Preparation of2,2,5,7-tetrafluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 30) and2,2,5,7-tetrafluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 31)

As shown in Step 1 of Scheme 12, to a stirred solution of2-bromo-1,3-difluoro-5-methoxybenzene (20.0 g, 90.1 mmol) in anhydrousTHF (200 mL) under an atmosphere of nitrogen was added n-BuLi (2.5 M inhexane, 39.6 mL, 99.1 mmol,) dropwise at −78° C. After addition wascomplete, stirring was continued at −78° C. for 15 minutes andhexafluorobenzene (25.1 g, 135.1 mmol) was added dropwise at −78° C. Theresulting mixture was warmed to room temperature, stirred for 2 hoursunder nitrogen, diluted with water, and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure, andpurified by flash chromatography (0%-10% ethyl acetate in petroleumether) to afford 2,2′,3,4,5,6,6′-heptafluoro-4′-methoxy-1,1′-biphenyl(9.0 g, 26% yield) as a white solid: GCMS calculated for (C₁₃H₅F₇O),310.0; found, 310.0.

As shown in Step 2 of Scheme 12, to a stirred solution of2,2′,3,4,5,6,6′-heptafluoro-4′-methoxy-1,1′-biphenyl (8.0 g, 25.8 mmol)in DCM (20 mL) and concentrated H₂SO₄ (80 mL) was added KNO₃ (2.6 g,25.8 mmol) in portions at 0° C. The resulting solution was stirred at20° C. for 16 hours under nitrogen, diluted with water, and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered, concentrated underreduced pressure, and purified by flash chromatography (0%-25% ethylacetate in petroleum ether) to afford2,2′,3,4,5,6,6′-heptafluoro-4′-methoxy-3′-nitro-1,1′-biphenyl (Compound1012, 5.5 g, 54% yield) as a yellow solid: GCMS (ESI) calculated for(C₁₃H₄F₇NO₃), 355.0; found, 355.0.

As shown in Step 3 of Scheme 12, to a stirred solution of2,2′,3,4,5,6,6′-heptafluoro-4′-methoxy-3′-nitro-1,1′-biphenyl (5.5 g,15.5 mmol) in DCM (70 mL) under a nitrogen atmosphere was added BBr₃(19.4 g, 77.4 mmol) dropwise at 0° C. The solution was stirred at 0° C.for 2 hours under nitrogen, diluted with water, and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to afford2,2′,3′,4′,5′,6,6′-heptafluoro-3-nitro-[1,1′-biphenyl]-4-ol (Compound1013, 4.9 g, crude) as yellow oil: MS (ESI) calculated for (C₁₂H₂F₇NO₃)[M−1]⁻, 339.9; found, 339.9. This material was used as is in subsequentreactions.

As shown in Step 4 of Scheme 12, to a stirred solution of2,2′,3′,4′,5′,6,6′-heptafluoro-3-nitro-[1,1′-biphenyl]-4-ol (4.9 g, 14.4mmol) in EtOH (30 mL) and H₂O (30 mL) was added Na₂S₂O₄ (12.5 g, 71.8mmol) in portions at 20° C. The resulting mixture was stirred at 100° C.for 2 hours under nitrogen, diluted with water, and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered, concentrated under reduced pressure,and purified by flash chromatography (0%-30% ethyl acetate in petroleumether) to afford3-amino-2,2′,3′,4′,5′,6,6′-heptafluoro-[1,1′-biphenyl]-4-ol (Compound1014, 3.9 g, 78% yield) as a yellow solid: MS (ESI) calculated for(C₁₂H₄F₇NO) [M+1]⁺, 312.0; found, 311.9.

As shown in Step 5 of Scheme 12, to a stirred solution of3-amino-2,2′,3′,4′,5′,6,6′-heptafluoro-[1,1′-biphenyl]-4-ol (3.9 g, 12.5mmol) and TEA (2.5 g, 25.1 mmol) in EtOAc (50 mL) was added and ethyl2-bromo-2,2-difluoroacetate (5.1 g, 25.1 mmol) in portions at 20° C. Theresulting mixture was stirred at 50° C. for 16 hours under nitrogen,cooled to room temperature, diluted with water, and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered, concentrated under vacuum, andpurified by reversed-phase flash chromatography (5%-70% acetonitrile inwater) to afford2-bromo-2,2-difluoro-N-(2,2′,3′,4′,5′,6,6′-heptafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide(Compound 1015, 1.5 g, 17% yield): MS (ESI) calculated for (C₁₄H₃BrF₉NO)[M−1]⁻, 465.9; found, 465.8.

As shown in Step 6 of Scheme 12, to a stirred solution of2-bromo-2,2-difluoro-N-(2,2′,3′,4′,5′,6,6′-heptafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide(1.0 g, 2.1 mmol) in DMF (10 mL) was added K₂CO₃ (591 mg, 4.27 mmol) inportions at 20° C. The resulting mixture was stirred at 50° C. for 2hours under nitrogen, diluted with water, and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered, concentrated under reduced pressure,and purified by flash chromatography (0%-20% ethyl acetate in petroleumether) to afford2,2,5,7-tetrafluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 30, 590 mg, 71% yield) as a yellow solid: MS (ESI) calculatedfor (C₁₄H₂F₉NO₂) [M−1]⁻, 385.9; found, 385.9; ¹H-NMR (400 MHz, DMSO-d₆)δ 12.53 (s, 1H), 7.63 (d, J=9.6 Hz, 1H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ−76.31, −116.25, −124.01, −139.00, −151.21, −161.25.

As shown in Step 7 of Scheme 12, to a stirred solution of2,2,5,7-tetrafluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(50 mg, 0.13 mmol) in DMF (1 mL) were added propargyl bromide (17 mg,0.14 mmol) and K₂CO₃ (20 mg, 0.14 mmol at 20° C. The resulting solutionwas stirred at 20° C. for 16 hours under nitrogen, then purified byreversed-phase preparative HPLC using the following conditions—Column:Xselect CSH C18 OBD Column 30×150 mm 5 μm; gradient: 60%-72%acetonitrile/0.1% aq. formic acid, to afford2,2,5,7-tetrafluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 31, 28 mg, 51% yield) as a white solid: GCMS calculated for(C₁₇H₄F₉NO₂), 425.0; found, 425.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.80 (d,J=9.2 Hz, 1H), 4.82 (d, J=2.8 Hz, 2H), 3.46 (s, 1H); ¹⁹F-NMR (376 MHz,DMSO-d₆) δ −78.21, −112.89, −117.49, −138.75, −150.73, −161.14.

Example 11. Preparation of4-(3,3-difluoroallyl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 32)

As shown in Scheme 13, to a solution of2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(500 mg, 1.35 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 49mg, 1.22 mmol) in portions at 0° C. under a nitrogen atmosphere. Themixture was stirred at 0° C. for 30 minutes under a nitrogen atmospherefollowed by the dropwise addition of 3-bromo-3,3-difluoroprop-1-ene (255mg, 1.65 mmol) at 0° C. The mixture was warmed to room temperature,stirred for 16 hours under nitrogen, diluted with water, and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered, concentrated underreduced pressure, and purified by reversed-phase flash chromatography(5%-55% acetonitrile in water) to afford4-(3,3-difluoroallyl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 32, 200 mg, 40% yield) as a white solid: GCMS calculated for(C₁₇H₅F₁₀NO₂), 445.0; found, 445.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.76 (d,J=9.6 Hz, 1H), 7.65 (d, J=6.4 Hz, 1H), 4.94-4.76 (m, 1H), 4.72-4.63 (m,2H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −74.97, −85.19, −115.92, −140.67,−153.18, −162.08.

Example 12. Preparation of2,2,7-trifluoro-6-(perfluorophenyl)-4-phenethyl-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 33)

As shown in Scheme 14, to a solution of2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(200 mg, 0.54 mmol) and (2-bromoethyl)benzene (150 mg, 0.81 mmol) inacetonitrile (2 mL) was added K₂CO₃ (150 mg, 1.08 mmol) and NaI (41 mg,0.27 mmol) at 20° C. The resulting solution was stirred at 80° C. for 16hours, cooled to room temperature, diluted with water, and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered, concentrated underreduced pressure, and purified by flash chromatography (0%-25% ethylacetate in petroleum ether) to afford2,2,7-trifluoro-6-(perfluorophenyl)-4-phenethyl-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 33, 200 mg, 74% yield) as a white solid: MS (ESI) calculatedfor (C₂₂H₁₁F₈NO₂) [M+1]⁺, 474.0; found, 474.0; ¹H-NMR (400 MHz,methanol-d₄) δ 7.37 (m, 2H), 7.26-7.16 (m, 5H), 4.33 (t, J=7.2 Hz, 2H),3.03 (t, J=7.2 Hz, 2H); ¹⁹F-NMR (376 MHz, methanol-d₄) δ −79.18,−117.29, −142.37, −156.38, −164.90.

Example 13. Preparation of2,2,7-trifluoro-4-(2-methylbut-3-yn-2-yl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 34) and2,2,7-trifluoro-4-(3-methylbuta-1,2-dien-1-yl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 35)

As shown in Scheme 15, to a stirred solution of2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(300 mg, 0.81 mmol) and 2-methylbut-3-yn-2-ol (342 mg, 4.07 mmol) intetrahydrofuran (4 mL) were sequentially added PPh₃ (1.1 g, 4.07 mmol)and DIAD (822 mg, 4.07 mmol) at 23° C. under nitrogen. The resultingsolution was stirred at 80° C. for 16 hours under nitrogen, cooled toroom temperature, diluted with water, and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure, andpurified by reversed-phase flash chromatography (5%-65%acetonitrile/water) to afford a mixture of compounds. The crude mixturewas further purified by reversed-phase preparative HPLC using thefollowing conditions—Column: XSelect CSH Prep C18 OBD Column, 19×250 mm,5 m; gradient: 80% to 90% MeOH/0.1% aq. formic acid, to afford2,2,7-trifluoro-4-(2-methylbut-3-yn-2-yl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 34, 25.3 mg, 7% yield) as a yellow semi-solid: GCMS calculatedfor (C₁₉H₉F₈NO₂), 435.0; found, 435.1; ¹H-NMR (400 MHz, DMSO-d₆) δ 8.02(d, J=6.8 Hz, 1H), 7.79 (d, J=9.2 Hz, 1H), 3.89 (s, 1H), 1.99 (s, 6H);¹⁹F-NMR (377 MHz, DMSO-d₆) δ −78.25, −114.71, −140.13, 153.50, −162.20.Also recovered as a later eluting compounds was2,2,7-trifluoro-4-(3-methylbuta-1,2-dien-1-yl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 35, 81.5 mg, 22% yield) as a white semi-solid: GCMS calculatedfor (C₁₉H₉F₈NO₂), 435.0; found, 435.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.78(d, J=9.6 Hz, 1H), 7.68 (d, J=6.4 Hz, 1H), 6.48 (s, 1H), 1.81 (s, 6H);¹⁹F-NMR (377 MHz, DMSO-d₆) δ −74.90, −115.58, −140.75, 153.23, −162.07.

Example 14. Preparation of2,2,7-trifluoro-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 36) and2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 37)

As shown in Step 1 of Scheme 16, to a solution of1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (20.0 g, 80.0 mmol),1,2,3,5-tetrafluorobenzene (36.0 g, 24.0 mmol), K₃PO₄ (33.9 g, 160mmol),chloro[(diadamantan-1-yl)(n-butyl)phosphino][2-aminao-1,1-biphenyl-2-yl]palladium(II)(CataCXium A Pd G2, 2.7 g, 4.0 mmol),bis(adamantan-1-yl)(butyl)phosphane (CataCXium A, 1.4 g, 4.0 mmol) indioxane (150 mL) was stirred at 90° C. for 16 hours under an atmosphereof nitrogen. The solvent was removed under reduced pressure and theresidue purified by reversed-phase flash column chromatography (5%-52%acetonitrile/water) to afford2,2′,3,4,6-pentafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl (Compound 1016,11.0 g, 38% yield) as a light yellow solid: GCMS calculated forC₁₃H₆F₅NO₃, 319.0; found, 319.0.

As shown in Step 2 of Scheme 16, to a stirred mixture of2,2′,3,4,6-pentafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl (1.0 g, 3.13mmol) in DCM (10 mL) was added boron tribromide (3.9 g, 15.7 mmol)dropwise at 0° C. under an atmosphere of nitrogen. The mixture wasstirred at 0° C. for 3 hours, diluted with water, and extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure to afford2,2′,3′,4′,6′-pentafluoro-5-nitro-[1,1′-biphenyl]-4-ol (Compound 1017,790 mg, 74% yield) as a brown solid: MS (ESI) calculated for(C₁₂H₄F₅NO₃) [M−1]⁻, 304.0; found, 303.9.

As shown in Step 3 of Scheme 16, to a stirred solution of2,2′,3′,4′,6′-pentafluoro-5-nitro-[1,1′-biphenyl]-4-ol (790 mg, 2.58mmol) in water (5 mL) and EtOH (5 mL) was added sodium hyposulfite (2.0g, 12.94 mmol). The resulting mixture was stirred at 100° C. for 2hours, cooled to room temperature, diluted with water, and extractedwith dichloromethane. The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by flash chromatography(0%-25% ethyl acetate/petroleum ether) to afford5-amino-2,2′,3′,4′,6′-pentafluoro-[1,1′-biphenyl]-4-ol (Compound 1018,580 mg, 59% yield) as a yellow solid: MS (ESI) calculated for(C₁₂H₆F₅NO) [M−1]⁻, 274.0; found, 274.0.

As shown in Step 4 of Scheme 16, to a solution of5-amino-2,2′,3′,4′,6′-pentafluoro-[1,1′-biphenyl]-4-ol (580 mg, 2.10mmol) and triethylamine (427 mg, 4.21 mmol) in EtOAc (5 mL) was addedethyl 2-bromo-2,2-difluoroacetate (856 mg, 4.21 mmol). The resultingmixture was stirred at 80° C. for 2 hours, cooled to room temperature,diluted with water, and extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to afford2-bromo-2,2-difluoro-N-(2′,3′,4′,6,6′-pentafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide(Compound 1019, 800 mg, 75% yield) as a brown oil: MS (ESI) calculatedfor (C₁₄H₅BrF₇NO₂) [M−1]⁻, 429.9; found, 430.0.

As shown in Step 5 of Scheme 16, a stirred solution of2-bromo-2,2-difluoro-N-(2′,3′,4′,6,6′-pentafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide(870 mg, 2.01 mmol) and K₂CO₃ (417 mg, 3.02 mmol) in DMF (10 mL) wasstirred at 50° C. for 2 hours, cooled to room temperature, diluted withwater, and extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filtered,and concentrated under reduced pressure. The residue was purified byreversed-phase flash chromatography (5%-80% acetonitrile/water) toafford2,2,7-trifluoro-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 36, 250 mg, 31% yield) as a brown solid: MS (ESI) calculatedfor (C₁₄H₄F₇NO₂) [M−1]⁻, 350.0; found, 350.2; ¹H-NMR (400 MHz, DMSO-d₆)δ 12.14 (s, 1H), 7.71-7.65 (m, 1H), 7.62 (d, J=9.6 Hz, 1H), 7.20 (d,J=6.4 Hz, 1H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −75.34, −115.87, −116.95,−131.54, −134.11, −164.81.

As shown in Step 6 of Scheme 16, to a solution of2,2,7-trifluoro-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(100 mg, 0.28 mmol) and K₂CO₃ (79 mg, 0.57 mmol) in DMF (1 mL) was addedpropargyl bromide (68 mg, 0.57 mmol). The resulting mixture was stirredat 25° C. for 16 hours then purified by reversed-phase flashchromatography (5%-70% acetonitrile/water) to afford2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 37, 47 mg, 42% yield) as a white solid: GCMS calculated for(C₁₇H₆F₇NO₂), 389.0, found, 389.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.82-7.70(m, 3H), 4.88 (d, J=2.4 Hz, 2H), 3.43 (t, J=2.4 Hz, 1H); ¹⁹F-NMR (376MHz, DMSO-d₆) δ −74.99, −115.19, −115.78, −131.27, −133.64, −164.84.

Example 15. Preparation of6-bromo-2,2,7-trifluoro-4-(4-methoxybenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1024)

As shown in Step 1 of Scheme 17, to a solution of1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (30.0 g, 0.12 mol) in MeOH(300 mL) and acetic acid (30 mL, 0.52 mol) was added Zn powder (39.5 g,0.6 mol) in portions at 0° C. The resulting solution was then stirred at20° C. for 16 hours, filtered, diluted with water, and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by flash chromatography (0%-50% ethylacetate/petroleum ether) to afford 5-bromo-4-fluoro-2-methoxyaniline(Compound 1020, 27.0 g, 78% yield) as a yellow solid: MS (ESI)calculated for (C₇H₇BrFNO) [M−1]⁻, 218.0; found, 218.0.

As shown in Step 2 of Scheme 17, to a solution of5-bromo-4-fluoro-2-methoxyaniline (27.0 g, 122.70 mmol) in DCM (270 mL)was added BBr₃ (154 g, 614 mmol) in portions at 0° C. The resultingsolution was stirred at 20° C. for 16 hours, diluted by the slowaddition of ice/water, and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered, concentrated under reduced pressure, and purified byflash chromatography (0%-60% ethyl acetate/petroleum ether) to afford2-amino-4-bromo-5-fluorophenol (Compound 1021, 25.0 g, 89% yield) as abrown solid: MS (ESI) calculated for (C₆H₅BrFNO) [M−1], 204.0; found,204.0.

As shown in Step 3 of Scheme 17, to a solution of2-amino-4-bromo-5-fluorophenol (18.0 g, 87.4 mmol) and ethyl2-bromo-2,2-difluoroacetate (35.5 g, 175 mmol) in EtOAc (180 mL) wasadded triethylamine (17.6 g, 175 mmol) at 20° C. The resulting solutionwas stirred at 50° C. for 2 hours, cooled to room temperature, dilutedwith water, and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered, concentrated under reduced pressure, and purified by flashchromatography (0%-40% ethyl acetate/petroleum ether) to afford2-bromo-N-(5-bromo-4-fluoro-2-hydroxyphenyl)-2,2-difluoroacetamide(Compound 1022, 11.0 g, 31% yield) as a brown solid: MS (ESI) calculatedfor (C₈H₄Br₂F₃NO₂) [M−1]⁻, 360.0; found, 360.0.

As shown in Step 4 of Scheme 17, to a solution of2-bromo-N-(5-bromo-4-fluoro-2-hydroxyphenyl)-2,2-difluoroacetamide (7.0g, 19.3 mmol) in DMF (70 mL) was added K₂CO₃ (5.3 g, 38.6 mmol) at 20°C. The resulting solution was stirred at 50° C. for 16 hours, cooled toroom temperature, diluted with water, and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure, andpurified by flash chromatography (0%-30% ethyl acetate/petroleum ether)to afford 6-bromo-2,2,7-trifluoro-4H-1,4-benzoxazin-3-one (Compound1023, 4.0 g, 66% yield) as a brown solid: MS (ESI) calculated for(C₈H₃BrF₃NO₂) [M−1]⁻, 280.0; found, 280.0.

As shown in Step 5 of Scheme 17, to a solution of6-bromo-2,2,7-trifluoro-4H-1,4-benzoxazin-3-one (2.0 g, 7.09 mmol) inDMF (20 mL) were added p-methoxybenzyl chloride (1.6 g, 10.7 mmol) andK₂CO₃ (1.9 g, 14.2 mmol) at 20° C. The resulting solution was stirred at20° C. for 16 hours, diluted with water, and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered, concentrated under reduced pressure,and purified by flash column chromatography (0%-30% ethylacetate/petroleum ether) to afford6-bromo-2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-1,4-benzoxazin-3-one(Compound 1024, 2.5 g, 78% yield) as a yellow solid: GCMS calculated for(C₁₆H₁₁BrF₃NO₃), 401.0; found, 401.0.

Example 16. Preparation of2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 38)

As shown in Step 1 of Scheme 18, a mixture of2,3,4,6-tetrafluorophenylboronic acid (1.0 g, 5.15 mmol), H₂O₂ (30%)(877 mg, 25.8 mmol) in acetic acid (2 mL) and water (2 mL) was stirredat 25° C. for 16 hours under an atmosphere of nitrogen, diluted withwater, and extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filtered,and concentrated under reduced pressure to afford2,3,4,6-tetrafluorophenol (Compound 1025, 800 mg) as a colorless oil: MS(ESI) calculated for (C₆H₂F₄O) [M−1]⁻, 165.0; found, 165.0. Thismaterial was used in subsequent reactions as is.

As shown in Step 2 of Scheme 18, to a stirred mixture of2,3,4,6-tetrafluorophenol (800 mg, 4.81 mmol), K₂CO₃ (1.0 g, 7.23 mmol)in DMF (4 mL) was added benzyl bromide (0.90 g, 5.63 mmol) dropwise at25° C. under an atmosphere of nitrogen. The resulting mixture wasstirred at 25° C. for 16 hours under nitrogen, diluted with water, andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered, concentratedunder reduced pressure, and purified by reversed-phase flashchromatography (5%-78% acetonitrile/water) to afford2-(benzyloxy)-1,3,4,5-tetrafluorobenzene (Compound 1026, 480 mg, 38%yield) as a colorless oil: GCMS calculated for (C₁₃H₈F₄O), 256.1; found,256.0.

As shown in Step 3 of Scheme 18, to a solution of2-(benzyloxy)-1,3,4,5-tetrafluorobenzene (669 mg, 2.61 mmol),6-bromo-2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-1,4-benzoxazin-3-one(700 mg, 1.74 mmol) and K₂CO₃ (481 mg, 3.48 mmol) in dioxane (2 mL) wereadded bis(adamantan-1-yl)(butyl)phosphane (62 mg, 0.17 mmol) andchloro[(diadamantan-1-yl)(n-butyl)phosphino][2-amino-1,1-biphenyl-2-yl]palladium(II)(116 mg, 0.17 mmol) at 20° C. The mixture was stirred at 110° C. for 16hours under nitrogen, cooled to room temperature, and purified by flashchromatography (0%-20% ethyl acetate/petroleum ether), then furtherpurified by reversed-phase flash chromatography (5%-84%acetonitrile/water) to afford6-[3-(benzyloxy)-2,4,5,6-tetrafluorophenyl]-2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-1,4-benzoxazin-3-one(Compound 1027, 400 mg, 39% yield) as a brown solid: GCMS calculated for(C₂₉H₁₈F₇NO₄), 577.1; found, 577.1.

As shown in Step 4 of Scheme 18, to a stirred mixture of6-[3-(benzyloxy)-2,4,5,6-tetrafluorophenyl]-2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-1,4-benzoxazin-3-one(440 mg, 0.76 mmol) in methanol (10 mL) was added Pd/C (48.6 mg, 0.45mmol) under an atmosphere of nitrogen. The atmosphere was evacuated andcharged with hydrogen three times then stirred at 25° C. for 2 hoursunder a hydrogen atmosphere. After this time, the hydrogen atmospherewas removed, the mixture filtered, and the filter cake washed with MeOH.The filtrate was collected and concentrated under reduced pressure toafford2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-1,4-benzoxazin-3-one(Compound 1028, 380 mg, 95% yield) as a brown solid: MS (ESI) calculatedfor (C₂₂H₁₂F₇NO₄) [M−1]⁻, 486.1; found, 485.9.

As shown in Step 5 of Scheme 18, to a stirred mixture of2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-1,4-benzoxazin-3-one(340 mg, 0.69 mmol) in DMF (3 mL) were added methyl iodide (119 mg, 0.84mmol) and K₂CO₃ (145 mg, 1.04 mmol) at 25° C. under an atmosphere ofnitrogen. The resulting mixture was stirred at 25° C. for 2 hours underan atmosphere of nitrogen, diluted with water, and extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered, concentrated underreduced pressure, and purified by reversed-phase flash chromatography(5%-28% acetonitrile/water) to afford2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-1,4-benzoxazin-3-one(Compound 1029, 300 mg, 85% yield) as a colorless oil: GCMS calculatedfor (C₂₃H₁₄F₇NO₄), 501.1; found, 501.1.

As shown in Step 6 of Scheme 18, to a mixture of2,2,7-trifluoro-4-[(4-methoxyphenyl)methyl]-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-1,4-benzoxazin-3-one(300 mg, 0.59 mmol) in DCM (2 mL) were added trifluoromethanesulfonicacid (898 mg, 6.0 mmol) and TFA (682 mg, 6.0 mmol). The resultingmixture was stirred at 20° C. for 2 hours under an atmosphere ofnitrogen, diluted with water, and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure, andpurified by reversed-phase flash chromatography (5%-55%acetonitrile/water) to afford2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-4H-1,4-benzoxazin-3-one(Compound 1030, 200 mg, 83% yield) as a yellow oil: MS (ESI) calculatedfor (C₁₅H₆F₇NO₃) [M−1]⁻, 381.0; found, 381.0.

As shown in Step 7 of Scheme 18, a mixture of2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-4H-1,4-benzoxazin-3-one(180 mg, 0.47 mmol), propargyl bromide (84.2 mg, 0.71 mmol) and K₂CO₃(131 mg, 0.94 mmol) in DMF (1 mL) was stirred at 25° C. for 2 hoursunder an atmosphere of nitrogen, diluted with water, and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered, concentrated under reducedpressure, and purified by reversed-phase flash chromatography (5%-64%acetonitrile/water) to afford2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-1,4-benzoxazin-3-one(Compound 38, 150 mg, 80% yield) as a yellow oil: GCMS calculated for(C₁₈H₈F₇NO₃), 419.0; found, 419.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.7-7.71(m, 2H), 4.88 (d, J=2.4 Hz, 2H), 4.02 (s, 3H), 3.44 (s, 1H); ¹⁹F NMR(377 MHz, DMSO-d₆) δ −74.94, −115.60, −134.37, −142.53, −148.47,−163.57.

Example 17. Preparation of2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 39)

As shown in Step 1 of Scheme 19, to a stirred solution of1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (10.0 g, 40.0 mmol) in dioxane(100 mL) were added 2,3,5,6-tetrafluoroanisole (10.8 g, 60.00 mmol),chloro[(diadamantan-1-yl)(n-butyl)phosphino][2-amino-1,1-biphenyl-2-yl]palladium(II)(1.3 g, 2.0 mmol), bis(adamantan-1-yl)(butyl)phosphane (0.70 g, 2.0mmol), and K₂CO₃ (11.1 g, 80.0 mmol). The resulting mixture was stirredat 90° C. for 16 hours under an atmosphere of nitrogen, cooled to roomtemperature, diluted with water, and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure, andpurified by flash chromatography (0%-10% ethyl acetate/petroleum ether)to afford 2,2′,3,5,6-pentafluoro-4,4′-dimethoxy-5′-nitro-1,1′-biphenyl(Compound 1031, 10.0 g, 72% yield) as a yellow solid: CGMS calculatedfor (C₁₄H₈F₅NO₄), 349.0; found, 349.0.

As shown in Step 2 of Scheme 19, to a stirred solution of2,2′,3,5,6-pentafluoro-4,4′-dimethoxy-5′-nitro-1,1′-biphenyl (5.0 g,14.3 mmol) in DCM (100 mL) was added BBr₃ (17.9 g, 71.6 mmol) dropwiseat 0° C. The resulting mixture was stirred at 20° C. for 2 hours underan atmosphere of nitrogen, quenched with MeOH at 0° C., diluted withwater, extracted with ethyl acetate, and the combined organicsconcentrated under reduced pressure. The residue was purified by flashchromatography (0%-5% MeOH/DCM) to afford2,2′,3,5,6-pentafluoro-5′-nitro-[1,1′-biphenyl]-4,4′-diol (Compound1032, 4.0 g, 87% yield) as a yellow solid: MS (ESI) calculated for(C₁₂H₄F₅NO₄) [M−1]⁻, 320.0; found, 320.0.

As shown in Step 3 of Scheme 19, to a stirred solution of2,2′,3,5,6-pentafluoro-5′-nitro-[1,1′-biphenyl]-4,4′-diol (4.5 g, 14.01mmol) in MeOH (50 mL) was added Pd/C (450 mg, 4.23 mmol) under anatmosphere of nitrogen. The atmosphere was replaced with hydrogen andthe resulting mixture stirred at 20° C. for 2 hours under a hydrogenatmosphere. After removal of the hydrogen atmosphere, the mixture wasfiltered and the filter cake washed with MeOH. The filtrate wasconcentrated under reduced pressure to afford5′-amino-2,2′,3,5,6-pentafluoro-[1,1′-biphenyl]-4,4′-diol (Compound1033, 4.0 g, 98% yield) as a dark green solid: MS (ESI) calculated for(C₁₂H₆F₅NO₂) [M−1]⁻, 290.0; found, 290.0.

As shown in Step 4 of Scheme 19, to a stirred solution of5′-amino-2,2′,3,5,6-pentafluoro-[1,1′-biphenyl]-4,4′-diol (4.0 g, 13.7mmol) in MeOH (40 mL) were added ethyl 2-bromo-2,2-difluoroacetate (8.4g, 41.21 mmol) and triethylamine (4.2 g, 41.2 mmol). The resultingmixture was stirred at 50° C. for 16 hours under an atmosphere ofnitrogen, cooled to room temperature, diluted with water, and extractedwith ethyl acetate. The combined organics were dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure, andpurified by flash chromatography (0%-7% MeOH/DCM) to afford2-bromo-2,2-difluoro-N-{2′,3′,5′,6,6′-pentafluoro-4,4′-dihydroxy-[1,1′-biphenyl]-3-yl}acetamide(Compound 1034, 3.3 g, 53% yield) as a yellow solid: MS (ESI) calculatedfor (C₁₄H₅BrF₇NO₃) [M−1]⁻, 446.0; found, 446.0.

As shown in Step 5 of Scheme 19, to a stirred solution of2-bromo-2,2-difluoro-N-{2′,3′,5′,6,6′-pentafluoro-4,4′-dihydroxy-[1,1′-biphenyl]-3-yl}acetamide(3.3 g, 7.37 mmol) in DMF (20 mL) was added K₂CO₃ (1.5 g, 11.05 mmol).The resulting mixture was stirred at 50° C. for 2 hours under anatmosphere of nitrogen, cooled to room temperature, diluted with water,and extracted with ethyl acetate. The combined organics were dried oversodium sulfate, filtered, concentrated under reduced pressure, andpurified by reversed-phase flash column chromatography (5%-50%acetonitrile/water) to afford2,2,7-trifluoro-6-(2,3,5,6-tetrafluoro-4-hydroxyphenyl)-4H-1,4-benzoxazin-3-one(Compound 1035, 1.5 g, 56% yield) as a yellow solid: MS (ESI) calculatedfor (C₁₄H₄F₇NO₃) [M−1]⁻, 366.0; found, 366.0.

As shown in Step 6 of Scheme 19, to a stirred mixture of2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-4H-1,4-benzoxazin-3-one(50 mg, 0.14 mmol) in DMF (2 mL) was added propargyl bromide (16.2 mg,0.14 mmol) dropwise at 0° C. under an atmosphere of nitrogen. Theresulting mixture was stirred at 25° C. for 2 hours under an atmosphereof nitrogen, diluted with water, and extracted with ethyl acetate. Thecombined organics were dried over sodium sulfate, filtered, concentratedunder reduced pressure, and purified by flash chromatography (0%-28%ethyl acetate/petroleum ether) to afford2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-1,4-benzoxazin-3-one(Compound 39, 26 mg, 51% yield) as an off-white solid: MS (ESI)calculated for (C₁₇H₆F₇NO₃) [M−1]⁻, 404.0; found, 403.9; ¹H-NMR (400MHz, DMSO-d₆) δ 11.94 (s, 1H), 7.74-7.68 (m, 2H), 4.88 (d, J=2.4 Hz,2H), 3.43 (t, J=2.4 Hz, 1H). ¹⁹F-NMR (377 MHz, DMSO-d₆) δ −75.03,−115.61, −143.82, −161.43. Also isolated from the chromatographicpurification were2,2,7-trifluoro-6-(2,3,5,6-tetrafluoro-4-(prop-2-yn-1-yloxy)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 67): MS (ESI) calculated for (C₁₇H₆F₇NO₃) [M−1]⁻ 404.0, found403.9; ¹H-NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 1H), 7.67-7.64 (m, 1H),7.28-7.22 (m, 1H), 5.08 (s, 2H), 3.81 (s, 1H). ¹⁹F-NMR (377 MHz,DMSO-d₆) δ −75.23, −116.77, −142.59, −155.59 and2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-(prop-2-yn-1-yloxy)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 68) GCMS calculated for (C₂₀H₈F₇NO₃) 443.0, found 443.1;¹H-NMR (400 MHz, DMSO-d₆) δ 7.86-7.67 (m, 2H), 5.10 (s, 2H), 4.88 (s,2H), 3.81 (s, 1H), 3.45 (s, 1H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −74.86,−115.59, −141.92, −155.51.

Example 18. Preparation of2,2,7-trifluoro-6-(2,3,5,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 40) and2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 41)

As shown in Step 1 of Scheme 20, to a stirred mixture ofdicyclohexyl(2′,6′-dimethoxy[1,1′-biphenyl]-2-yl)phosphane (Sphos, 990mg, 2.40 mmol), Pd(OAc)₂ (270 mg, 1.20 mmol) and K₂CO₃ (3.3 g, 24.0mmol) in isopropyl acetate (20 mL) was added 1,2,4,5-tetrafluorobenzene(3.6 g, 24.0 mmol) at room temperature under an atmosphere of nitrogen.The resulting mixture was stirred at room temperature for 10 minutesunder an atmosphere of nitrogen and1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (3.0 g, 12.0 mmol) inisopropyl acetate (10 mL) was added dropwise over 0.5 hours at 80° C.The mixture was stirred at 80° C. for additional 2 hours, the volatilesremoved under reduced pressure, and the residue purified by flashchromatography (0%-40% EtOAc/petroleum ether) to afford2,2′,3,5,6-pentafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl (Compound 1036,1.5 g, 35% yield) as a purple solid: GCMS calculated for (C₁₃H₆F₅NO₃),319.0; found, 319.0

As shown in Step 2 of Scheme 20, to a mixture of2,2′,3,5,6-pentafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl (1.5 g, 4.69mmol) in DCM (15 mL) at −78° C. was added BBr₃ (5.8 g, 23.49 mmol)dropwise. The resulting mixture was stirred at −78° C. for 3 hours underan atmosphere of nitrogen, diluted with water at room temperature, andextracted with CH₂Cl₂. The combined organics were dried over sodiumsulfate, filtered, and concentrated to about 20% volume under reducedpressure, filtered again, and the filtrate concentrated under reducedpressure to afford2,2′,3′,5′,6′-pentafluoro-5-nitro-[1,1′-biphenyl]-4-ol (Compound 1037,1.3 g) as a brown solid: MS (ESI) calculated for (C₁₂H₄F₅NO₃) [M−1]⁻,304.0; found, 304.0. This material was used in subsequent steps withoutfurther purification.

As shown in Step 3 of Scheme 20, to a stirred solution of2,2′,3′,5′,6′-pentafluoro-5-nitro-[1,1′-biphenyl]-4-ol (1.4 g, 4.58mmol) in EtOH (10 mL) and H₂O (3 mL) was added sodium hyposulfite (3.9g, 22.91 mmol) in portions. The resulting mixture was stirred at 100° C.for 1 hour under an atmosphere of nitrogen, cooled to room temperature,diluted with water, and extracted with ethyl acetate. The combinedorganics dried over sodium sulfate, filtered, and concentrated underreduced pressure to afford5-amino-2,2′,3′,5′,6′-pentafluoro-[1,1′-biphenyl]-4-ol (Compound 1038,1.2 g) as a yellow solid: MS (ESI) calculated for (C₁₂H₅F₆NO) [M−1]⁻,292.1; found, 292.1. This material was used as is in subsequentreactions.

As shown in Step 4 of Scheme 20, to a solution of5-amino-2,2′,3′,5′,6′-pentafluoro-[1,1′-biphenyl]-4-ol (500 mg, 1.81mmol) and triethylamine (184 mg, 1.81 mmol) in EtOAc (5 mL) was addedethyl 2-bromo-2,2-difluoroacetate (369 mg, 1.81 mmol). The resultingmixture was stirred at 80° C. for 5 hours under an atmosphere ofnitrogen, cooled to room temperature diluted with water, and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered, concentrated underreduced pressure, and purified by flash chromatography (0%-38%EtOAc/petroleum ether) to afford2-bromo-2,2-difluoro-N-(2′,3′,5′,6,6′-pentafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide (Compound 1039, 300 mg, 38% yield) as a brown solid: MS (ESI)calculated for (C₁₄H₅BrF₇NO₂) [M+1]⁺, 431.9; found, 431.9.

As shown in Step 5 of Scheme 20, a solution of2-bromo-2,2-difluoro-N-[2′,3′,5′,6,6′-pentafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl]acetamide (500 mg, 1.15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU, 178 mg, 1.16 mmol) in toluene (5 ml) were stirred at 80° C. for 2hours under an atmosphere of nitrogen, cooled to room temperature,diluted with water, and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered, concentrated under reduced pressure, and purified byflash chromatography (0%-30% ethyl acetate/petroleum ether) to afford2,2,7-trifluoro-6-(2,3,5,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 40, 230 mg, 55% yield) as a brown solid: MS(ESI) calculated for (C₁₄H₄F₇NO₂) [M−1]⁻, 350.0; found, 350.0; ¹H-NMR(400 MHz, DMSO-d₆) δ 12.20 (s, 1H), 8.07 (m, 1H), 7.70-7.62 (m, 1H),7.24 (d, J=6.4 Hz, 1H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −75.21, −116.80,−138.87, −141.58.

As shown in Step 6 of Scheme 20, to a solution of2,2,7-trifluoro-6-(2,3,5,6-tetrafluorophenyl)-4H-1,4-benzoxazin-3-one(50 mg, 0.14 mmol) and K₂CO₃ (22 mg, 0.15 mmol) in DMF (1 mL) was addedpropargyl bromide (19 mg, 0.15 mmol). The resulting mixture was stirredat room temperature for 2 hours under an atmosphere of nitrogen followedby purification via reversed-phase HPLC (53% to 68% acetonitrile/10 mMaqueous NH₄HCO₃) to afford 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(²,3,5,6-tetrafluorophenyl)-2H-benzo[b][1,4] oxazin-3(4H)-one (Compound 41,42.1 mg, 75% yield) as a yellow oil: GCMS calculated for (C₁₇H₆F₇NO₂),389.0; found, 389.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 8.18-8.05 (m, 1H),7.83-7.74 (m, 2H), 4.87 (d, J=2.4 Hz, 2H), 3.45 (t, J=2.4 Hz, 1H);¹⁹F-NMR (376 MHz, DMSO-d₆) δ −74.83, −115.67, −138.83, −141.01.

Example 19. Preparation of2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 42) and2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 43)

As shown in Step 1 of Scheme 21, to a stirred mixture of2,2′,3,4,6-pentafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl (1.0 g, 3.13mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (LiHMDS,6.27 mmol, 1M in THF) dropwise at −78° C. under an atmosphere ofnitrogen. The resulting mixture was stirred at −78° C. for 30 minutesand methyl iodide (0.7 g, 4.70 mmol) was added at −78° C. under anatmosphere of nitrogen. The mixture was stirred at −78° C. for 4 hoursunder nitrogen, diluted with water, and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure, andpurified by flash chromatography (0%-50% ethyl acetate/petroleum ether)to afford2,2′,3,4,6-pentafluoro-4′-methoxy-5-methyl-5′-nitro-1,1′-biphenyl(Compound 1040, 800 mg, 77% yield) as a yellow solid: GCMS calculatedfor (C₁₄H₈F₅NO₃), 333.0; found, 333.0.

As shown in Step 2 of Scheme 21, to a stirred mixture of2,2′,3,4,6-pentafluoro-4′-methoxy-5-methyl-5′-nitro-1,1′-biphenyl (800mg, 2.40 mmol) in DCM (20 mL) was added boron tribromide (3.7 g, 12.00mmol) dropwise at 0° C. under an atmosphere of nitrogen. The resultingmixture was stirred at 0° C. for 2 hours, diluted with water, andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered, concentratedunder reduced pressure, and purified by flash chromatography (0%-50%ethyl acetate/petroleum ether) to afford methyl2-(6-amino-2,2,7-trifluoro-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate(Compound 1041, 710.0 mg, 93% yield) as a yellow oil: MS (ESI)calculated for (C₁₃H₆F₅NO₃) [M−1]⁻, 318.0; found, 318.0.

As shown in Step 3 of Scheme 21, to a stirred mixture of2,2′,3′,4′,6′-pentafluoro-5′-methyl-5-nitro-[1,1′-biphenyl]-4-ol (710mg, 2.22 mmol) in acetic acid (0.2 mL) and MeOH (20 mL) was added zincpowder (727 mg, 11.1 mmol). The resulting mixture was stirred at roomtemperature for 2 hours under an atmosphere of nitrogen, filtered,diluted with water, and extracted with ethyl acetate. The combinedorganic layers were washed with NaHCO₃, dried over anhydrous sodiumsulfate, filtered, concentrated under reduced pressure, and purified byflash chromatography (0%-50% ethyl acetate/petroleum ether) to afford5-amino-2,2′,3′,4′,6′-pentafluoro-5′-methyl-[1,1′-biphenyl]-4-ol(Compound 1042, 560 mg, 87% yield) as a brown solid: MS (ESI) calculatedfor (C₁₃H₈F₅NO) [M−1]⁻, 288.0; found, 288.0.

As shown in Step 4 of Scheme 21, to a stirred mixture of5-amino-2,2′,3′,4′,6′-pentafluoro-5′-methyl-[1,1′-biphenyl]-4-ol (600mg, 2.08 mmol) in ethyl acetate (15 mL) were added ethyl2-bromo-2,2-difluoroacetate (632 mg, 3.11 mmol) and triethylamine (420mg, 4.15 mmol). The resulting mixture was stirred at 50° C. for 16 hoursunder an atmosphere of nitrogen, cooled to room temperature, dilutedwith water, and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered, concentrated under reduced pressure, and purified by flashchromatography (0%-50% ethyl acetate/petroleum ether) to afford2-bromo-2,2-difluoro-N-(2′,3′,4′,6,6′-pentafluoro-4-hydroxy-5′-methyl-[1,1′-biphenyl]-3-yl)acetamide(Compound 1043, 550 mg, 59% yield) as a brown solid: MS (ESI) calculatedfor (C₁₅H₇BrF₇NO₂) [M−1]⁻, 444.0; found, 444.0.

As shown in Step 5 of Scheme 21, to a stirred mixture of2-bromo-2,2-difluoro-N-(2′,3′,4′,6,6′-pentafluoro-4-hydroxy-5′-methyl-[1,1′-biphenyl]-3-yl)acetamide(550 mg, 1.23 mmol) in DMF (10 mL) was added K₂CO₃ (511 mg, 3.70 mmol).The resulting mixture was stirred at 80° C. for 2 hours under anatmosphere of nitrogen, cooled to room temperature, diluted with water,and extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered,concentrated under reduced pressure, and purified by flashchromatography (0%-50% ethyl acetate/petroleum ether) to afford2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 42, 360 mg, 80% yield) as a brown solid; MS (ESI) calculatedfor (C₁₅H₆F₇NO₂) [M−1]⁻, 364.0; found, 364.0; ¹H-NMR (400 MHz, DMSO-d₆)δ 12.17 (s, 1H), 7.64 (d, J=9.6 Hz, 1H), 7.18 (d, J=6.4 Hz, 1H), 2.24(s, 3H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −75.25, −116.88, −120.24, −135.31,−138.86, −165.49.

As shown in Step 6 of Scheme 21, to a stirred solution of2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(180.0 mg, 0.49 mmol) in DMF (6 mL) were added propargyl bromide (70.4mg, 0.59 mmol) and K₂CO₃ (204.4 mg, 1.48 mmol). The resulting mixturewas stirred at room temperature for 2 hours under an atmosphere ofnitrogen, diluted with water, and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure, andpurified by reversed-phase flash chromatography (5%-50%acetonitrile/water) to afford2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-methylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 43, 148.0 mg, 75% yield) as a colorless oil: GCMS calculatedfor (C₁₈H₇F₇NO₂), 403.0; found, 403.0; ¹H-NMR (400 MHz, DMSO-d₆) δ7.77-7.69 (m, 2H), 4.88 (s, 2H), 3.45-3.43 (m, 1H), 2.28-2.23 (m, 3H);¹⁹F-NMR (400 MHz, DMSO-d₆) δ −74.98, −115.72, −119.75, −134.88, −138.34,−165.51.

Example 20. Preparation of4-benzyl-2,2,7-trifluoro-6-(2,3,5,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 44)

As shown in Scheme 22, to a mixture of2,2,7-trifluoro-6-(2,3,5,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.14 mmol) and K₂CO₃ (39 mg, 0.28 mmol) in DMF(1 mL) was added benzyl bromide (29 mg, 0.17 mmol). The resultingmixture was stirred at room temperature for 16 hours under an atmosphereof nitrogen, then purified by reversed-phase HPLC (60% to 72%acetonitrile/10 mM aqueous Nh₄HCO₃) to afford4-benzyl-2,2,7-trifluoro-6-(2,3,5,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 44, 43 mg, 68% yield) as a white solid: GCMS calculated for(C₂₁H₁₀F₇NO₂), 441.1; found, 441.1; ¹H-NMR (400 MHz, DMSO-d₆) δ 8.07 (m,1H), 7.78-7.75 (m, 1H), 7.73-7.68 (m, 1H), 7.39-7.26 (m, 5H), 5.28 (s,2H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −74.87, −115.89, −138.90, −141.20.

Example 21. Preparation of2,2,7-trifluoro-4-methyl-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 45) and2,2,7-trifluoro-4-methyl-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 46)

As shown in Step 1 of Scheme 23, to a degassed mixture of2,2′,3,4,6-pentafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl (3.0 g, 9.40mmol) in DMF (30 mL) were added CuCL₂ (0.6 g, 4.70 mmol) and t-BuOLi(1.5 g, 18.80 mmol) under an oxygen atmosphere. The mixture was stirredat room temperature for 16 hours under an 02 atmosphere, diluted withwater, acidified to pH 2-4 with formic acid, and extracted with ethylacetate. The combined organics were washed with brine, dried overanhydrous sodium sulfate, filtered, concentrated under reduced pressure,and purified by reversed-phase flash chromatography (30%-50%acetonitrile/water) to afford2,2′,4,5,6-pentafluoro-4′-methoxy-5′-nitro-[1,1′-biphenyl]-3-ol(Compound 1044, 850 mg, 25% yield) as a yellow solid: MS (ESI)calculated for (C₁₃H₆F₅NO₄) [M−1]⁻, 334.0; found, 334.0.

As shown in Step 2 of Scheme 23, to a solution of2,2′,4,5,6-pentafluoro-4′-methoxy-5′-nitro-[1,1′-biphenyl]-3-ol (850 mg,2.54 mmol) in DCM (10 mL) was added boron tribromide (3.2 g, 12.7 mmol)dropwise at −78° C. under an atmosphere of nitrogen. The resultingmixture was stirred at −78° C. for 3 hours under an atmosphere ofnitrogen, warmed to room temperature, then stirred for additional 2hours. The mixture was diluted with water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to afford2,2′,4,5,6-pentafluoro-5′-nitro-[1,1′-biphenyl]-3,4′-diol (Compound1045, 850 mg, 78% yield) as a yellow solid. MS (ESI) calculated for(C₁₂H₄F₅NO₄) [M−1]⁻, 320.0; found, 319.8.

As shown in Step 3 of Scheme 23, to a solution of2,2′,4,5,6-pentafluoro-5′-nitro-[1,1′-biphenyl]-3,4′-diol (850 mg, 2.70mmol) in ethanol (9 mL) and H₂O (3 mL) was added sodium hyposulfite (2.4g, 14.01 mmol). The resulting mixture was stirred at 100° C. for 2hours, cooled to room temperature, diluted with water, and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure to afford5′-amino-2,2′,4,5,6-pentafluoro-[1,1′-biphenyl]-3,4′-diol (Compound1046, 850 mg) as a yellow solid: MS (ESI) calculated for (C₁₂H₆F₅NO₂)[M−1]⁻, 290.0; found, 289.9. This material was used in subsequentreactions as is.

As shown in Step 4 of Scheme 23, to a mixture of5′-amino-2,2′,4,5,6-pentafluoro-[1,1′-biphenyl]-3,4′-diol (850 mg, 2.92mmol) in ethyl acetate (10 mL) were added triethylamine (325 mg, 3.21mmol) and ethyl 2-bromo-2,2-difluoroacetate (652 mg, 3.21 mmol) under anatmosphere of nitrogen. The resulting mixture was stirred at 50° C. for3 hours under nitrogen, cooled to room temperature, diluted with water,and extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to afford2-bromo-2,2-difluoro-N-(2′,3′,4′,6,6′-pentafluoro-4,5′-dihydroxy-[1,1′-biphenyl]-3-yl)acetamide (Compound 1047, 950 mg, crude) as a yellow oil. MS (ESI)calculated for (C₁₄H₅BrF₇NO₃) [M−1]⁻, 445.9; found, 445.9.

As shown in Step 5 of Scheme 23, to a mixture of2-bromo-2,2-difluoro-N-(2′,3′,4′,6,6′-pentafluoro-4,5′-dihydroxy-[1,1′-biphenyl]-3-yl)acetamide (950 mg, 2.12 mmol) in DMF (10 mL) was added K₂CO₃ (879 mg,6.36 mmol). The resulting mixture was stirred at 80° C. for 2 hoursunder a nitrogen atmosphere, cooled to room temperature, diluted withwater, acidified to pH 1-3 with formic acid, and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered, concentrated under reduced pressure,and purified by flash chromatography (20%-60% acetonitrile/water) toafford2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1048, 150 mg, 19% yield) as a brown yellow solid: MS (ESI)calculated for (C₁₄H₄F₇NO₃) [M−1]⁻, 366.0; found, 366.0; ¹H-NMR (400MHz, DMSO-d₆) δ 12.14 (s, 1H), 11.03 (s, 1H), 7.63 (d, J=9.6 Hz, 1H),7.17 (d, J=6.8 Hz, 1H); ⁷⁹F-NMR (376 MHz, DMSO-d₆) δ −75.27, −116.82,−138.63, −150.19, −152.90, −165.02.

As shown in Step 6 of Scheme 23, to a solution of2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (150 mg, 0.41 mmol) and triethylamine (54 mg, 0.53mmol) in DCM (1 mL), MeOH (0.1 mL) and acetonitrile (1 mL) was addedtrimethylsilyldiazomethane (0.49 mL, 2 M in hexane) at 0° C. under anatmosphere of nitrogen. The resulting mixture was stirred at roomtemperature for 16 hours, concentrated under reduced pressure, andpurified by reversed-phase flash chromatography (20%-40%acetonitrile/water) to afford2,2,7-trifluoro-4-methyl-6-(2,3,4,6-tetrafluoro-5-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 45, 31 mg, 20% yield) as a yellow oil: GCMS calculated for(C₁₆H₈F₇NO₃), 395.0; found, 395.1; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.85-7.65(m, 2H), 4.02 (s, 3H), 3.42 (s, 3H). Also isolated was2,2,7-trifluoro-4-methyl-6-(2,3,4,6-tetrafluoro-5-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 46, 6.7 mg, 4%) as a yellow oil: GCMScalculated for (C₁₅H₆F₇NO₃), 380.0; found, 379.9; ¹H-NMR (300 MHz,DMSO-d₆) δ 7.79-7.66 (m, 2H), 3.63 (s, 3H).

Example 22. Preparation of 2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(²,3,4,6-tetrafluoro-5-vinylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 47)

As shown in Step 1 of Scheme 24, to a stirred mixture of2,2′,3,4,6-pentafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl (1.0 g, 3.13mmol) in DMF (10 mL) were added t-BuOLi (0.30 g, 3.76 mmol) and iodine(0.80 g, 3.13 mmol). The mixture was stirred at 80° C. for 2 hours underan atmosphere of nitrogen, cooled to room temperature, diluted withwater, and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filtered,concentrated under reduced pressure, and purified by reversed-phaseflash chromatography (0%-70% acetonitrile/water) to afford2,2′,3,4,6-pentafluoro-5-iodo-4′-methoxy-5′-nitro-1,1′-biphenyl(Compound 1049, 660 mg, 47% yield) as a yellow solid: GCMS calculatedfor (C₁₃H₅F₅INO₃), 444.9; found, 444.9.

As shown in Step 2 of Scheme 24, to a stirred mixture of2,2′,3,4,6-pentafluoro-5-iodo-4′-methoxy-5′-nitro-1,1′-biphenyl (660 mg,1.48 mmol) in DCM (15 mL) was added boron tribromide (1.8 g, 7.41 mmol)dropwise at 0° C. under an atmosphere of nitrogen. The resulting mixturewas stirred at 0° C. for 2 hours, diluted with water, and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered, concentrated under reducedpressure, and purified by flash chromatography (0%-15% ethylacetate/petroleum ether) to afford2,2′,3′,4′,6′-pentafluoro-5′-iodo-5-nitro-[1,1′-biphenyl]-4-ol (Compound1050, 580 mg, 90% yield) as a brown oil: MS (ESI) calculated for(C₁₂H₃F₅₁NO₃) [M−1]⁻, 430.0; found, 430.0.

As shown in Step 3 of Scheme 24, to a stirred mixture of2,2′,3′,4′,6′-pentafluoro-5′-iodo-5-nitro-[1,1′-biphenyl]-4-ol (580 mg,1.32 mmol) in EtOAc (20 mL) was added SnCl₂ (1.3 g, 7.14 mmol). Themixture was stirred at 70° C. for 2 hours under an atmosphere ofnitrogen, cooled to room temperature, diluted with water, and extractedwith ethyl acetate. The combined organic layers were washed with 1M HCland water, dried over anhydrous sodium sulfate, filtered, concentratedunder reduced pressure, and purified by flash chromatography (0%-35%ethyl acetate/petroleum ether) to afford5-amino-2,2′,3′,4′,6′-pentafluoro-5′-iodo-[1,1′-biphenyl]-4-ol (Compound1051, 330 mg, 56% yield) as a yellow solid: MS (ESI) calculated for(C₁₂H₅F₅₁NO) [M−1]⁻, 400.0; found, 400.0.

As shown in Step 4 of Scheme 24, to a stirred mixture of5-amino-2,2′,3′,4′,6′-pentafluoro-5′-iodo-[1,1′-biphenyl]-4-ol (280 mg,0.69 mmol) in THF (10 mL) were added bromodifluoroacetyl chloride (203mg, 1.04 mmol) and triethylamine (141 mg, 1.39 mmol). The mixture wasstirred at 100° C. for 1 hour under an atmosphere of nitrogen, cooled toroom temperature, diluted with water, and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure, andpurified by flash column chromatography (0%-35% ethyl acetate/petroleumether) to afford2-bromo-2,2-difluoro-N-(2′,3′,4′,6,6′-pentafluoro-4-hydroxy-5′-iodo-[1,1′-biphenyl]-3-yl)acetamide(Compound 1052, 340 mg, 87% yield) as a yellow solid: MS (ESI)calculated for (C₁₄H₄BrF₇INO₂) [M−1]⁻, 556.0; found, 556.0.

As shown in Step 5 of Scheme 24, to a stirred mixture of2-bromo-2,2-difluoro-N-(2′,3′,4′,6,6′-pentafluoro-4-hydroxy-5′-iodo-[1,1′-biphenyl]-3-yl)acetamide(310 mg, 0.56 mmol) in DMF (10 mL) was added K₂CO₃ (230 mg, 1.66 mmol).The mixture was stirred at 80° C. for 2 hours, cooled to roomtemperature, diluted with water, and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure, andpurified by flash column chromatography (0%-35% ethyl acetate/petroleumether) to afford2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-iodophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1053, 200 mg, 75% yield) as a yellow oil: MS (ESI) calculatedfor (C₁₄H₃F₇₁NO₂) [M−1]⁻, 476.0; found, 476.0.

As shown in Step 6 of Scheme 24, to a stirred mixture of2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-iodophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(100 mg, 0.21 mmol) in dioxane (5 mL) and H₂O (0.5 mL) were added2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (39 mg, 0.25 mmol),Pd(dppf)Cl₂ (15 mg, 0.02 mmol), and K₃PO₄ (133 mg, 0.63 mmol). Themixture was stirred at 80° C. for 16 hours under an atmosphere ofnitrogen, cooled to room temperature, diluted with water, and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered, concentrated underreduced pressure, and purified by preparative-TLC (1:5 EtOAc/petroleumether) to afford2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-vinylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1054, 70 mg, 88% yield) as a yellow oil: MS (ESI) calculatedfor (C₁₆H₆F₇NO₂) [M−1]⁻, 376.0; found, 376.0.

As shown in Step 7 of Scheme 24, to a stirred solution of2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-vinylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(60 mg, 0.16 mmol) in DMF (3 mL) were added propargyl bromide (23 mg,0.19 mmol) and K₂CO₃ (66 mg, 0.48 mmol). The resulting mixture wasstirred at room temperature for 2 hours, diluted with water, andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered, concentratedunder reduced pressure, and purified by flash column chromatography(0%-15% ethyl acetate/petroleum ether) to afford2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-vinylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 47, 37 mg, 56% yield) as a light oil: GCMS calculated for(C₁₉H₈F₇NO₂), 415.0; found, 415.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.76-7.74(m, 2H), 6.78-6.66 (m, 1H), 6.05 (d, J=17.6 Hz, 1H), 5.81 (d, J=11.6 Hz,1H), 4.87 (s, 2H), 3.44 (s, 1H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −74.96,−115.67, −119.12, −135.03, −135.41, −164.64.

Example 23. Preparation of6-(3-ethyl-2,4,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 48)

As shown in Step 1 of Scheme 25, to a stirred mixture of2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-vinylphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(80 mg, 0.21 mmol) in MeOH (2 mL) and THF (2 mL) was added Pd/C (10%, 20mg) under nitrogen. The atmosphere was replaced with hydrogen and themixture stirred at room temperature for 4 hours. After removal of thehydrogen atmosphere, the solids were filtered out through a Celite pad,the filtrate collected, and the volatiles removed under reduced pressureto afford6-(3-ethyl-2,4,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1055, 50 mg, 60% yield) as a brown oil: MS (ESI) calculatedfor (C₁₆H₈F₇NO₂) [M−1], 378.0; found, 378.0.

As shown in Step 2 of Scheme 25, to a stirred solution of6-(3-ethyl-2,4,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one(50 mg, 0.13 mmol) in DMF (2 mL) were added propargyl bromide (19 mg,0.15 mmol) and K₂CO₃ (55 mg, 0.39 mmol). The resulting mixture wasstirred at 25° C. for 2 hours under an atmosphere of nitrogen, dilutedwith water, and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered, concentrated under reduced pressure, and purified byreversed-phase flash column chromatography (20%-70% acetonitrile/waterto afford6-(3-ethyl-2,4,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 48, 13 mg, 24% yield) as a colorless oil: GCMS calculated for(C₁₉H₁₀F₇NO₂), 417.1; found, 417.0; ¹H-NMR (400 MHz, methanol-d₄) δ7.59-7.57 (m, 1H), 7.40-7.36 (m, 1H), 4.91-4.89 (m, 2H), 2.87 (s, 1H),2.88-2.77 (m, 2H), 1.29-1.24 (m, 3H); ¹⁹F-NMR (376 MHz, methanol-d₄) δ−78.88, −116.82, −123.84, −139.44, −139.86, −167.94.

Example 24. Preparation of2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-(methylthio)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 49)

As shown in Scheme 26, to a stirred solution of2,2,7-trifluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(200 mg, 0.49 mmol) in dioxane (3 mL) was added sodium thiomethoxide(34.0 mg, 0.49 mmol). The resulting mixture was stirred at 20° C. for 2hours, diluted with water, and extracted with ethyl acetate. Thecombined organics were dried over sodium sulfate, filtered, concentratedunder reduced pressure, and purified by flash chromatography (0%-10%ethyl acetate/petroleum ether) to afford2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-(methylthio)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 49, 40 mg, 19% yield) as a white solid: GCMS calculated for(C₁₈H₈F₇NO₂S) 435.0; found 434.9; ¹H-NMR (400 MHz, chloroform-d) δ 7.32(d, J=6.0 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 4.82 (d, J=2.4 Hz, 2H), 2.62(s, 3H), 2.39 (s, 1H); ¹⁹F-NMR (376 MHz, chloroform-d) δ −77.00,−113.18, −134.54, −140.64.

Example 25. Preparation of2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 50)

As shown in Scheme 27, to a stirred solution of2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(50 mg, 0.12 mmol) in DMF (2 mL) were added methyl iodide (21 mg, 0.15mmol) and K₂CO₃ (26 mg, 0.18 mmol). The mixture was stirred at roomtemperature for 2 hours under a nitrogen atmosphere, diluted with water,and extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered,concentrated under reduced pressure, and purified by preparative—TLC(25% EtOAc/petroleum ether) and further purified by reversed-phase flashchromatography with (5%-60% acetonitrile in water) to afford2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(²,3,5,6-tetrafluoro-4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 50) (13 mg, 25% yield) as a white solid: MS (ESI) calculatedfor (C₁₈H₈F₇NO₃) [M+1]⁺, 420.0; found 420.0; ¹H-NMR (400 MHz, DMSO-d₆) δ7.87-7.64 (m, 2H), 4.88 (s, 2H), 4.15 (s, 3H), 3.38 (s, 1H); ¹⁹F-NMR(376 MHz, DMSO-d₆) δ −74.92, −115.62, −142.27, −157.65.

Example 26. Preparation of6-(4-ethoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 51)

As shown in Step 1 of Scheme 28, to a solution of2,2,7-trifluoro-6-(2,3,5,6-tetrafluoro-4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(1.0 g, 2.72 mmol) in DMF (10 mL) were added K₂CO₃ (1.1 g, 8.16 mmol)and 4-methoxybenzyl chloride (1.0 g, 6.8 mmol). The mixture was stirredat 20° C. for 2 hours under a nitrogen atmosphere, diluted with water,and extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered,concentrated under reduced pressure, and purified by flashchromatography (0%-50% ethyl acetate in petroleum ether) to afford2,2,7-trifluoro-4-(4-methoxybenzyl)-6-(2,3,5,6-tetrafluoro-4-((4-methoxybenzyl)oxy)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1056, 804 mg, 48% yield) as a white solid: MS (ESI) calculatedfor (C₃₀H₂₀F₇NO₅) [M−1]⁻, 606.0; found 606.2.

As shown in Step 2 of Scheme 15, to a solution of2,2,7-trifluoro-4-(4-methoxybenzyl)-6-(2,3,5,6-tetrafluoro-4-((4-methoxybenzyl)oxy)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(804 mg, 1.41 mmol) in methanol (10 mL) was added Pd/C (161 mg, 20%wt/wt) under a nitrogen atmosphere. The atmosphere was replaced withhydrogen gas and the mixture was stirred at 20° C. for 2 hours underhydrogen. The hydrogen was removed, the mixture filtered, and thefiltrated concentrated under reduced pressure to afford2,2,7-trifluoro-4-(4-methoxybenzyl)-6-(2,3,5,6-tetrafluoro-4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1057, 750 mg, crude) as a yellow solid: MS (ESI) calculatedfor (C₂₂H₁₂F₇NO₄) [M−1]⁻, 486.0; found 486.1

As shown in Step 3 of Scheme 15, to a solution of2,2,7-trifluoro-4-(4-methoxybenzyl)-6-(2,3,5,6-tetrafluoro-4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(200 mg, 0.44 mmol) in DMF (3 mL) were added iodoethane (84 mg, 0.53mmol) and K₂CO₃ (93 mg, 0.66 mmol). The mixture was stirred at 20° C.for 1 hour under a nitrogen atmosphere, diluted with water, andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered, concentratedunder reduced pressure, and purified by flash chromatography (0%-50%ethyl acetate in petroleum ether) to afford6-(4-ethoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(4-methoxybenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1058. 160 mg, 97% yield) as a yellow solid: MS (ESI)calculated for (C₂₄H₁₆F₇NO₄) [M−1], 514.1; found 514.0.

As shown in Step 4 of Scheme 15, to a solution of6-(4-ethoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(4-methoxybenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(150 mg, 0.29 mmol) in DCM (2 mL) were added trifluoroacetic acid (332mg, 2.91 mmol) and trifluoromethanesulfonic acid (437 mg, 2.91 mmol).The mixture was stirred at 20° C. for 1 hour under a nitrogenatmosphere, diluted with water, and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure, andpurified by flash chromatography (0%-70% ethyl acetate in petroleumether) to afford6-(4-ethoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1059, 70 mg, 60% yield) as a yellow oil: MS (ESI) calculatedfor (C₁₆H₈F₇NO₃) [M−1]⁻, 394.0; found 394.0.

As shown in Step 5 of Scheme 15, to a solution of6-(4-ethoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one(68 mg, 0.17 mmol) in DMF (2 mL) were added K₂CO₃ (48 mg, 0.34 mmol) andpropargyl bromide (31 mg, 0.25 mmol). The mixture was stirred at 20° C.for 2 hours under a nitrogen atmosphere, diluted with water, andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered, concentratedunder reduced pressure, and purified by reversed-phase flashchromatography (5%-70% acetonitrile in water) to afford6-(4-ethoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 51, 59 mg, 78% yield) as a white solid: GCMS calculated for(C₁₉H₁₀F₇NO₃), 433.0; found, 433.1; ¹H-NMR (400 MHz, DMSO-d₆) δ7.80-7.72 (m, 2H), 4.88 (d, J=2.4 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 3.45(s, 1H), 1.39 (t, J=7.2 Hz, 3H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −74.88,−115.55, −142.21, −156.98.

Example 27. Preparation of7-fluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 52)

As shown in Step 1 of Scheme 29, to a solution of5-amino-2,2′,3′,4′,6′-pentafluoro-[1,1′-biphenyl]-4-ol (250 mg, 0.91mmol) in DME (1.5 mL) and H₂O (1.5 mL) was added NaHCO₃ (229 mg, 2.73mmol) at room temperature under a nitrogen atmosphere, followed by thedropwise addition of chloroacetyl chloride (154 mg, 1.36 mmol) at 0° C.The reaction was stirred at room temperature for 3 hours andconcentrated under reduced pressure to afford2-chloro-N-(2′,3′,4′,6,6′-pentafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide(Compound 1060, 250 mg, crude) as a brown solid: MS (ESI) calculated for(C₁₄H₇ClF₅NO₂) [M−1]⁻, 350.0; found, 350.0. This material was used as isin subsequent reactions.

As shown in Step 2 of Scheme 29, a mixture of2-chloro-N-(2′,3′,4′,6,6′-pentafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide(250 mg, 0.71 mmol) and K₂CO₃ (198 mg, 1.42 mmol) in DMF (3 mL) wasstirred at 50° C. for 1 hour under a nitrogen atmosphere, cooled to roomtemperature, diluted with water, and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure, andpurified by flash chromatography (0%-20% ethyl acetate in petroleumether) to afford7-fluoro-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1061, 210 mg, 94% yield) as a yellow solid: MS (ESI)calculated for (C₁₄H₆F₅NO₂) [M−1]⁻, 314.0; found, 314.0.

As shown in Step 3 of Scheme 29, to a stirred mixture of7-fluoro-6-(2,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(50 mg, 0.16 mmol) and K₂CO₃ (33 mg, 0.24 mmol) in DMF (1 mL) was addedpropargyl bromide (23 mg, 0.19 mmol). The mixture was stirred at roomtemperature for 2 hours under a nitrogen atmosphere then purified byreversed-phase flash chromatography (5%-65% acetonitrile in water) toafford 7-fluoro-4-(prop-2-yn-1-yl)-6-(²,3,4,6-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 52,27 mg, 48% yield) as a white solid: MS (ESI) calculated for (C₁₇H₈F₅NO₂)[M+1]⁺, 354.0; found, 354.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.77-7.67 (m,1H), 7.40 (d, J=6.8 Hz, 1H), 7.23 (d, J=9.6 Hz, 1H), 4.84 (d, J=1.2 Hz,2H), 4.75 (d, J=2.4 Hz, 2H), 3.33 (s, 1H); ¹⁹F-NMR (377 MHz, DMSO-d6) δ−115.26, −118.50, −132.08, −133.75, −165.01.

Example 28. Preparation of2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 53)

As shown in Step 1 of Scheme 30, to a degassed solution of6-bromo-2,2,7-trifluoro-4-(4-methoxybenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(300.0 mg, 0.74 mmol) in toluene (5 mL) and water (1 mL) were added2,3,4,5-tetrafluorophenylboronic acid (434 mg, 2.23 mmol), XPhos Pd G3(126 mg, 0.14 mmol), XPhos (71 mg, 0.14 mmol), Ag₂O (346 mg, 1.49 mmol)at 20° C. The resulting mixture was stirred for 16 hours at 90° C. undera nitrogen atmosphere followed by quenching by the addition of water.The aqueous layer was extracted with ethyl acetate, the combinedorganics dried over sodium sulfate, filtered, concentrated under reducedpressure, and purified by reversed-phase flash chromatography (5%-70%acetonitrile in water) to afford2,2,7-trifluoro-4-(4-methoxybenzyl)-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1062, 20 mg, 5% yield) as a yellow solid: GCMS calculated for(C₂₂H₁₂F₇NO₃) 471.0, found 471.0; ¹H-NMR (400 MHz, methanol-d4) δ7.31-7.28 (m, 2H), 7.29-7.19 (m, 2H), 7.18-7.06 (m, 1H), 6.95-6.83 (m,2H), 5.26 (s, 2H), 3.76 (s, 3H); ¹⁹F-NMR (376 MHz, methanol-d₄) δ−78.77, −78.85, −118.25, −141.39, −141.46, −158.09.

As shown in Step 2 of Scheme 30, To a solution of2,2,7-trifluoro-4-(4-methoxybenzyl)-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(50 mg, 0.11 mmol) in DCM (2.5 mL) were added TFA (121 mg, 1.06 mmol)and CF₃SO₃H (159 mg, 1.06 mmol). The resulting mixture was stirred at20° C. for 2 h before removal of the volatiles under reduced pressure.The residue was purified by silica gel column chromatography (0%-26%ethyl acetate in petroleum ether) and further purified bypreparative-HPLC using the following conditions—Column: XSelect CSH C18OBD Column 30×150 mm 5 μm; Mobile Phase A: ACN, Mobile Phase B: Water(0.1% formic acid); Flow rate: 60 mL/min; Gradient: 53% B to 63% B in 10min, then 63% B to afford2,2,7-trifluoro-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1063, 11 mg, 28% yield) as an off-white solid: MS (ESI)calculated for (C₁₄H₄F₇NO₂) [M−1]⁻ 350.0, found 349.9; ¹H-NMR (400 MHz,DMSO-d₆) δ 7.71-7.56 (m, 2H), 7.14 (d, J=6.9 Hz, 1H); ¹⁹F-NMR (376 MHz,DMSO-d₆) δ −75.54, −118.23, −139.87, −140.13, −155.38, −155.84.

As shown in Step 3 of Scheme 30, to a solution of2,2,7-trifluoro-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(70 mg, 0.20 mmol) in DMF (2 mL) were added propargyl bromide (36 mg,0.30 mmol) and K₂CO₃ (55 mg, 0.39 mmol). The resulting mixture wasstirred for 16 hours at 20° C. followed by purification byreversed-phase flash chromatography (5%-60% acetonitrile in water) toafford2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 53, 33 mg, 41% yield) as colorless oil: CGMS calculated for(C₁₇H₆F₇NO₂) 389.0, found 389.1; ¹H-NMR (400 MHz, CD₃OD) δ 7.61-7.55 (m,1H), 7.44-7.33 (m, 2H), 4.93 (s, 2H), 3.32 (s, 1H); ¹⁹F-NMR (376 MHz,CD₃OD) δ −78.93, −117.98, −141.37, −141.54, −157.99, −158.37.

Example 29. Preparation of7-fluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 54)

As shown in Step 1 of Scheme 31, a mixture of 1,2,3,4-tetrafluorobenzene(3 equiv.), 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (1 equiv.),Pd(OAc₂) (0.1 equiv.), di-tert-butylmethylphosphine (0.1 equiv.), andK₂CO₃ (1 equiv.) in dioxane are heated to 90° C. for 16 hours, cooled toroom temperature, diluted with water, and extracted with EtOAc. Thecombined extracts are washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residueis purified by reversed-phase flash chromatography to yield2,2′,3,4,5-pentafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl (Compound1064).

As shown in Step 2 of Scheme 31, to a stirred mixture of2,2′,3,4,5-pentafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl (1 equiv.) inDCM is added boron tribromide (5 equiv.) dropwise at 0° C. under anatmosphere of nitrogen. The mixture is stirred at 0° C. for 3 hours,diluted with water, and extracted with dichloromethane. The combinedorganic layers are washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to afford2,2′,3′,4′,5′-pentafluoro-5-nitro-[1,1′-biphenyl]-4-ol (Compound 1065).

As shown in Step 3 of Scheme 31, to a stirred solution of2,2′,3′,4′,5′-pentafluoro-5-nitro-[1,1′-biphenyl]-4-ol (1 equiv) in 1:1water/EtOH is added sodium hyposulfite (5 equiv.). The resulting mixtureis stirred at 100° C. for 2 hours, cooled to room temperature, dilutedwith water, and extracted with dichloromethane. The combined organiclayers are washed with brine, dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The residue ispurified by flash chromatography to afford5-amino-2,2′,3′,4′,5′-pentafluoro-[1,1′-biphenyl]-4-ol (Compound 1066).

As shown in Step 4 of Scheme 31, to a solution5-amino-2,2′,3′,4′,5′-pentafluoro-[1,1′-biphenyl]-4-ol (1 equiv.) in 1:1DME/H₂O is added NaHCO₃ (3 equiv.) at room temperature under a nitrogenatmosphere, followed by the dropwise addition of chloroacetyl chloride(1.5 equiv.) at 0° C. The reaction is stirred at room temperature for 3hours and concentrated under reduced pressure to afford2-chloro-N-(2′,3′,4′,5′,6-pentafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide(Compound 1067).

As shown in Step 5 of Scheme 31, a mixture of2-chloro-N-(2′,3′,4′,5′,6-pentafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)acetamide(1 equiv.) and K₂CO₃ (2 equiv.) in DMF (3 mL) is stirred at 50° C. for 1hour under a nitrogen atmosphere, cooled to room temperature, dilutedwith water, and extracted with ethyl acetate. The combined organiclayers are washed with brine, dried over anhydrous sodium sulfate,filtered, concentrated under reduced pressure, and purified by flashchromatography to afford7-fluoro-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1068).

As shown in Step 6 of Scheme 31, to a stirred mixture of7-fluoro-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(1 equiv.) and K₂CO₃ (1.5 equiv.) in DMF is added propargyl bromide (1.2equiv.). The mixture is stirred at room temperature for 2 hours under anitrogen atmosphere then purified by reversed-phase flash chromatographyto afford7-fluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,5-tetrafluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 54).

Example 30. Preparation of2,2-dichloro-7-fluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 55)

As shown in Step 1 of Scheme 32, chlorine gas (about 2 equiv.) isintroduced into a stirred suspension of7-fluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (1 equiv.)in PCl₃ (6 equiv.). After 2 hours at room temperature, the volatiles areremoved at atmospheric pressure via distillation to afford2,2-dichloro-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 1069).

As shown in Step 2 of Scheme 32, to a solution of2,2-dichloro-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (1 equiv.) in DMFare added K₂CO₃ (1.05 equiv.) and 3-bromoprop-1-yne (1.05 equiv.) atroom temperature under nitrogen. The mixture is stirred at roomtemperature for 8 hours, diluted with water, and extracted with ethylacetate. The combined organic layers are washed with brine, dried overanhydrous sodium sulfate, filtered, concentrated under reduced pressure,and purified by preparative reversed-phase HPLC to afford2,2-dichloro-7-fluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 55).

Example 31. Preparation of7-chloro-2,2-difluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 56)

As shown in Step 1 of Scheme 33, to a stirred solution of1-bromo-2-chloro-4-methoxybenzene (1 equiv.) in anhydrous THF (200 mL)under an atmosphere of nitrogen is added n-BuLi (2.5 M in hexane, 1.1equiv.) dropwise at −78° C. After addition is complete, stirring iscontinued at −78° C. for 15 minutes and hexafluorobenzene (1.5 equiv.)is added dropwise at −78° C. The resulting mixture is warmed to roomtemperature, stirred for 2 hours under nitrogen, diluted with water, andextracted with ethyl acetate. The combined organic layers are washedwith brine, dried over anhydrous sodium sulfate, filtered, concentratedunder reduced pressure, and purified by flash chromatography to afford2′-chloro-2,3,4,5,6-pentafluoro-4′-methoxy-1,1′-biphenyl (Compound1070).

As shown in Step 2 of Scheme 33, a solution of2′-chloro-2,3,4,5,6-pentafluoro-4′-methoxy-1,1′-biphenyl in nitric acidis stirred at 50° C. for 4 hours, diluted with water, and extracted withethyl acetate. The combined organic layers are washed with brine, driedover anhydrous sodium sulfate, filtered, concentrated under reducedpressure, and purified by flash chromatography to afford2′-chloro-2,3,4,5,6-pentafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl(Compound 1071).

As shown in Step 3 of Scheme 33, to a solution of5-bromo-4-chloro-2-methoxyaniline (1 equiv.) in DCM is added BBr₃ (5equiv.) in portions at 0° C. The resulting solution is stirred at 20° C.for 16 hours, diluted by the slow addition of ice/water, and extractedwith ethyl acetate. The combined organic layers are washed with brine,dried over anhydrous sodium sulfate, filtered, concentrated underreduced pressure, and purified by flash chromatography to afford2-chloro-2′,3′,4′,5′,6′-pentafluoro-5-nitro-[1,1′-biphenyl]-4-ol(Compound 1072).

As shown in Step 4 of Scheme 33, to a solution of2-chloro-2′,3′,4′,5′,6′-pentafluoro-5-nitro-[1,1′-biphenyl]-4-ol (1equiv.) in MeOH and acetic acid (4 equiv.) is added Zn powder (5 equiv.)in portions at 0° C. The resulting solution is stirred at 20° C. for 16hours, filtered, diluted with water, and extracted with ethyl acetate.The combined organic layers are washed with brine, dried over anhydroussodium sulfate, filtered, concentrated under reduced pressure, andpurified by flash chromatography to afford5-amino-2-chloro-2′,3′,4′,5′,6′-pentafluoro-[1,1′-biphenyl]-4-ol(Compound 1073).

As shown in Step 5 of Scheme 33, to a solution of5-amino-2-chloro-2′,3′,4′,5′,6′-pentafluoro-[1,1′-biphenyl]-4-ol (1equiv.) and ethyl 2-bromo-2,2-difluoroacetate (2 equiv.) in MeOH (180mL) is added triethylamine (2 equiv.) at 20° C. The resulting solutionis stirred at 50° C. for 2 hours, cooled to room temperature, dilutedwith water, and extracted with ethyl acetate. The combined organiclayers are washed with brine, dried over anhydrous sodium sulfate,filtered, concentrated under reduced pressure, and purified by flashchromatography (0%-40% ethyl acetate/petroleum ether) to afford2-bromo-N-(6-chloro-2′,3′,4′,5′,6′-pentafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)-2,2-difluoroacetamide(Compound 1074).

As shown in Step 6 of Scheme 33, to a solution of2-bromo-N-(6-chloro-2′,3′,4′,5′,6′-pentafluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)-2,2-difluoroacetamide(1 equiv.) in DMF is added K₂CO₃ (2 equiv.) at 20° C. The resultingsolution is stirred at 50° C. for 16 hours, cooled to room temperature,diluted with water, and extracted with ethyl acetate. The combinedorganic layers are washed with brine, dried over anhydrous sodiumsulfate, filtered, concentrated under reduced pressure, and purified byflash chromatography to afford7-chloro-2,2-difluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1075).

As shown in Step 7 of Scheme 33, to a solution of7-chloro-2,2-difluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(50 mg, 0.13 mmol) in DMF (1 mL) is added K₂CO₃ (1.5 equiv.) and themixture is stirred at 25° C. for 10 minutes, followed by the dropwiseaddition of propargyl bromide (1.5 equiv.) at room temperature. Themixture is stirred at room temperature for 2 hours followed bypurification by preparative reversed-phase HPLC to afford7-chloro-2,2-difluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 56).

Example 32. Preparation of6-(4-amino-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 57) andN-acetyl-N-(2,3,5,6-tetrafluoro-4-(2,2,7-trifluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)phenyl)acetamide(Compound 58)

As shown in Step 1 of Scheme 34, to solution of2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(380 mg, 1.03 mmol) in THF (4 mL) was added benzylamine (441 mg, 4.11mmol). The reaction mixture was stirred at 80° C. for 16 hours under anitrogen atmosphere, cooled to room temperature, diluted with water, andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered, concentratedunder reduced pressure, and purified by reversed-phase flashchromatography (5%-60% acetonitrile in water) to afford6-(4-(benzylamino)-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1076, 220 mg, 42% yield) as a yellow solid: MS (ESI)calculated for (C₂₁H₁₁F₇N₂O₂) [M+1]⁺ 457.1, found 457.1.

As shown in Step 2 of Scheme 34, to a solution of6-(4-(benzylamino)-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one(100 mg, 0.22 mmol) in MeOH (5 mL) was added Pd/C (12 mg, 0.11 mmol)under nitrogen. The nitrogen atmosphere was replaced with hydrogen andthe resulting solution stirred at 65° C. for 3 hours. The suspension wascooled, filtered and the filtrate collected and concentrated underreduced pressure. The residue was purified by reversed-phase flashchromatography (5%-53% acetonitrile in water) to afford6-(4-amino-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 1077, 70 mg, 87% yield) as a yellow solid: MS (ESI) calculatedfor (C₁₄H₅F₇N₂O₂) [M+1]⁺ 367.0, found 367.0.

As shown in Step 3 of Scheme 34, to a solution of6-(4-amino-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one(50 mg, 0.13 mmol) in DMF (1 mL) was added K₂CO₃ (28 mg, 0.20 mmol) andthe mixture was stirred at 25° C. for 10 minutes, followed by thedropwise addition of propargyl bromide (24 mg, 0.20 mmol) at roomtemperature. The mixture was stirred at room temperature for 2 hoursfollowed by purification by preparative HPLC using the followingconditions—Column: Xselect CSH C₁₈ OBD Column 30×150 mm 5 μm; MobilePhase A: ACN, Mobile Phase B: Water (0.1% FA); Gradient: 54% B to 62% Bin 10 minutes, then 62% B, to afford6-(4-amino-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 57, 20 mg, 35% yield) as a white solid: GCMS calculated for(C₁₇H₇F₇N₂O₂) 404.0, found 404.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.76-7.50(m, 2H), 6.33 (s, 2H), 4.89 (d, J=2.4 Hz, 2H), 3.43 (s, 1H); ¹⁹F-NMR(376 MHz, DMSO-d₆) δ −75.13, −115.56, −144.93, −161.62.

As shown in Step 4 of Scheme 34, to a stirred mixture of6-(4-amino-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(20 mg, 0.05 mmol) and DIEA (6.4 mg, 0.05 mmol) in THF (1 mL) was addedacetyl chloride (4 mg, 0.05 mmol) at 0° C. under a nitrogen atmosphere.The resulting mixture was stirred at room temperature for 16 hours. Thereaction was quenched by the addition of water and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was dissolved in DMF (1mL) and applied to a C-18 column and purified by reversed-phase flashchromatography (5%-65% acetonitrile in water) to affordN-acetyl-N-(2,3,5,6-tetrafluoro-4-(2,2,7-trifluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)phenyl)acetamide(Compound 58, 8 mg, 34% yield) as a yellow oil: MS (ESI) calculated for(C₂₁H₁₁F₇N₂O₄) [M+1]⁺ 89.1, found 489.0; ¹H-NMR (400 MHz, DMSO-d₆) δ7.89 (d, J=6.4 Hz, 1H), 7.86-7.74 (m, 1H), 4.88 (d, J=2.4 Hz, 2H), 3.50(s, 1H), 2.44 (s, 6H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −74.64, −115.17,−140.00, −145.66.

Example 33. Preparation of2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-(methylamino)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 59) andN-methyl-N-(2,3,5,6-tetrafluoro-4-(2,2,7-trifluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)phenyl)acetamide(Compound 60)

As shown in Step 1 of Scheme 35, a solution of2,2,7-trifluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(200 mg, 0.49 mmol) in methylamine (2M in THF) (3 mL) was stirred at 80°C. for 2 h under a nitrogen atmosphere. The resulting mixture wasconcentrated under reduced pressure and purified by preparative-HPLCusing the following conditions: X Bridge Prep Phenyl OBD Column (19×250mm, 5 m); Mobile Phase A, Water (0.1% formic acid), Mobile Phase B, ACN;Flow rate: 25 mL/min; Gradient: 55% B to 75% B in 10 min, then 75% B;Wavelength: 254 nm to produce2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-(methylamino)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 59, 105 mg, 51% yield) as a white solid: MS (ESI) calc'd for(C₁₈H₉F₇N₂O₂) [M−1]⁻ 417.0, found 417.0; ¹H-NMR (400 MHz, DMSO-d₆) δ7.76-7.58 (m, 2H), 6.36-6.21 (m, 1H), 4.88 (d, J=2.4 Hz, 2H), 3.48 (s,1H), 3.11-2.96 (m, 3H); ¹⁹F-NMR (377 MHz, DMSO-d₆) δ −75.10, −115.55,−144.56, −161.54.

As shown in Step 2 of Scheme 35, to a solution of2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,5,6-tetrafluoro-4-(methylamino)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(40 mg, 0.10 mmol) in THF (2 mL) were added acetyl chloride (15 mg, 0.19mmol) and DIEA (25 mg, 0.19 mmol) at 0° C. The resulting solution wasstirred at 80° C. for 16 hours under a nitrogen atmosphere, thenconcentrated under reduced pressure. The residue was purified byreversed-phase flash chromatography (5%-55% acetonitrile in water) toaffordN-methyl-N-(2,3,5,6-tetrafluoro-4-(2,2,7-trifluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)phenyl)acetamide(Compound 60, 30 mg, 68% yield) as a white solid: MS (ESI) calc'd for(C₂₀H₁₁F₇N₂O₃) [M+1]⁺ 461.0, found 461.0; ¹H-NMR (400 MHz, DMSO-d₆) δ7.91-7.68 (m, 2H), 4.88 (d, J=2.4 Hz, 2H), 3.53-3.39 (m, 3H), 3.19 (s,1H), 2.35-1.90 (m, 3H); ¹⁹F-NMR (376 MHz, DMSO-d₆) δ −74.74, −115.35,−141.16, −145.4.

Example 34. Preparation of6-(4-(dimethylamino)-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 61)

As shown in Scheme 36, a solution of2,2,7-trifluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(100 mg, 0.25 mmol) in methylamine (2M in THF) (3 mL) was stirred at 80°C. for 2 h under a nitrogen atmosphere. The resulting mixture wasconcentrated under reduced pressure and purified by reversed-phase flashchromatography (5%-60% acetonitrile in water) to afford6-(4-(dimethylamino)-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 61) (56 mg, 53% yield) as a white solid: MS (ESI) calc'd for(C₁₉H₁₁F₇N₂O₂) [M+1]⁺ 433.0, found 432.9; ¹H-NMR (400 MHz, DMSO-d₆) δ7.80-7.60 (m, 2H), 4.88 (d, J=2.4 Hz, 2H), 3.50-3.42 (m, 1H), 3.06-2.93(m, 6H); ¹⁹F-NMR (377 MHz, DMSO-d₆) δ −74.97, −115.58, −143.29, −151.61.

Example 35. Preparation of6-(4-(benzylamino)-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 62)

As shown in Scheme 37, To a stirred solution of2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(100 mg, 0.27 mmol) in THF (1.5 mL) was added phenylmethanamine (116 mg,1.08 mmol) at room temperature under a nitrogen atmosphere. Theresulting mixture was stirred at 80° C. for 16 hours under a nitrogenatmosphere then concentrated under reduced pressure. The residue wasapplied to a C18 column and purified by reversed-phase flashchromatography (5%-65% acetonitrile in water), then further purified bypreparative-HPLC using the following conditions: Column: XSelect CSHF-phenyl OBD Column, 19×250 mm, 5 μm; Mobile Phase A=water (0.05% formicacid), Mobile Phase B=ACN; Flow rate=25 mL/min; eluted with 60% B toafford6-(4-(benzylamino)-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 62, 29.5 mg, 24% yield) as a white solid: MS (ESI) calculatedfor (C₂₁H₁₁F₇N₂O₂) [M+1]⁺ 457.1, found 457.1; ¹H-NMR (400 MHz, DMSO-d₆)δ 12.09 (br, 1H), 7.57 (d, J=9.6 Hz, 1H), 7.36-7.34 (m, 4H), 7.30-7.21(m, 1H), 7.12 (d, J=6.8 Hz, 1H), 6.99 (s, 1H), 4.54 (d, J=6.0 Hz, 2H);¹⁹F-NMR (376 MHz, DMSO-d₆) δ −75.38, −116.61, −144.64, −144.70, −159.97.

Example 36. Preparation of6-(4-cyclopropoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 63) and6-(4-cyclopropoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[h][1,4]oxazin-3(4H)-one(Compound 64)

As shown in Step 1 of Scheme 38, to a solution of cyclopropanol (63 mg,1.08 mmol) in DMF (2 mL) was added NaH (43 mg, 1.08 mmol, 60%) at 0° C.The reaction mixture was stirred at 0° C. for 30 min under a nitrogenatmosphere and2,2,7-trifluoro-6-(2,3,4,5,6-pentafluorophenyl)-4H-1,4-benzoxazin-3-one(200 mg, 0.54 mmol) in DMF (1 mL) was added dropwise at 0° C. under anitrogen atmosphere. The resulting mixture was stirred at 20° C. for 2hours under a nitrogen atmosphere, followed by quenching the reactionwith water at 0° C. The aqueous layer was extracted with ethyl acetate,the combined organics dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (0%-26% ethyl acetate in petroleum ether) andfurther purified by reversed-phase flash chromatography (5%-50%acetonitrile in water) to afford6-(4-cyclopropoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 63, 70.0 mg, 35% yield) as a white solid: MS (ESI) calc'd for(C₁₇H₈F₇NO₃) [M−1]⁻ 406.0, found 405.9; ¹H-NMR (400 MHz, methanol-d₄) δ7.31 (d, J=9.6 Hz, 1H), 7.16 (d, J=6.4 Hz, 1H), 4.47-4.39 (m, 1H),0.96-0.89 (m, 2H), 0.81-0.72 (m, 2H); ¹⁹F-NMR (376 MHz, methanol-d₄) δ−78.94, −117.66, −144.45, −158.76.

As shown in Step 2 of Scheme 38, To a stirred solution of6-(4-cyclopropoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one(70 mg, 0.17 mmol) in DMF (1 mL) were added K₂CO₃ (36 mg, 0.26 mmol) andpropargyl bromide (25 mg, 0.20 mmol). The reaction mixture was stirredat room temperature for 2 hours under a nitrogen atmosphere, quenchedwith water, and the aqueous solution was extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue waspurified by reversed-phase flash chromatography (5%-68% acetonitrile inwater to afford6-(4-cyclopropoxy-2,3,5,6-tetrafluorophenyl)-2,2,7-trifluoro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 64, 23 mg, 29% yield) as a white solid: GCMS calculated for(C₂₀H₁₀F₇NO₃) 445.0, found 445.0; ¹H-NMR (400 MHz, DMSO-d₆) δ 7.88-7.59(m, 2H), 4.87 (d, J=2.4 Hz, 2H), 4.51-4.42 (m, 1H), 3.46-3.43 (m, 1H),0.94-0.88 (m, 2H), 0.81-0.73 (m, 2H); ¹⁹F-NMR (377 MHz, DMSO-d₆) δ−74.89, −115.55, −141.88, −156.42.

Example 37. Preparation of2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-(2-hydroxyethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 65) and2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-(2-hydroxyethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 66)

As shown in Step 1 of Scheme 39, To a solution of2,2′,3,4,6-pentafluoro-4′-methoxy-5′-nitro-1,1′-biphenyl (3.5 g, 10.92mmol) and 12 mmol equivalents of oxirane in THF (45 mL) was addedlithium hexamethyldisilazide (27.4 mL, 27.37 mmol) dropwise at −78° C.After addition was complete, the resulting mixture was warmed to roomtemperature and stirred for 12 h under a nitrogen atmosphere. Thereaction was quenched by the addition of water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum, andpurified by silica gel column chromatography, (0%-50% ethyl acetate inpetroleum ether) to afford2-(2,2′,4,5,6-pentafluoro-4′-methoxy-5′-nitro-[1,1′-biphenyl]-3-yl)ethan-1-ol(Compound 1078, 1.7 g, 42% yield) as a yellow oil: GCMS calculated for(C₁₅H₁₀F₅NO₄) 363.1, found 363.1

As shown in Step 2 of Scheme 39, To a solution of2-(2,2′,4,5,6-pentafluoro-4′-methoxy-5′-nitro-[1,1′-biphenyl]-3-yl)ethan-1-ol(1.7 g, 4.6 mmol) in DCM (15 mL) was added BBr₃ (2.2 mL, 23.0 mmol)dropwise at 0° C. The resulting mixture was stirred at 0° C. for 2 hoursunder a nitrogen atmosphere. The reaction mixture was quenched by theaddition of water and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (0%-30% ethyl acetate inpetroleum ether) to afford2,2′,3′,4′,6′-pentafluoro-5′-(2-hydroxyethyl)-5-nitro-[1,1′-biphenyl]-4-ol(Compound 1079, 690 mg, 42% yield) as a yellow solid: MS (ESI)calculated for (C₁₄H₈F₅NO₄) [M−1]⁻ 348.0, found 348.0.

As shown in Step 3 of Scheme 39, To a stirred solution of2,2′,3′,4′,6′-pentafluoro-5′-(2-hydroxyethyl)-5-nitro-[1,1′-biphenyl]-4-ol(690 mg, 1.97 mmol) in AcOH (0.5 mL) and MeOH (5 mL) was added Zn dust(642.5 mg, 9.88 mmol) in portions at 0° C. under a nitrogen atmosphere.The resulting mixture was stirred at 25° C. for 2 hours under a nitrogenatmosphere, quenched by the addition of water, extracted with ethylacetate, and washed with saturated NaHCO₃ three times. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (0%-50% ethyl acetatein petroleum ether) to afford5-amino-2,2′,3′,4′,6′-pentafluoro-5′-(2-hydroxyethyl)-[1,1′-biphenyl]-4-ol(Compound 1080, 450 mg, 71% yield) as a yellow solid: MS (ESI)calculated for (C₁₄H₁₀F₅NO₂) [M−1]⁻ 318.1, found 318.1.

As shown in Step 4 of Scheme 39, To a stirred solution of5-amino-2,2′,3′,4′,6′-pentafluoro-5′-(2-hydroxyethyl)-[1,1′-biphenyl]-4-ol(450 mg, 1.41 mmol) and methyl 2-bromo-2,2-difluoroacetate (346 mg, 1.83mmol) in MeOH (5 mL) was added TEA (143 mg, 1.41 mmol) at 25° C. under anitrogen atmosphere. The resulting mixture was stirred at 50° C. for 2hours under a nitrogen atmosphere. The resulting reaction mixture wasallowed to cool down to room temperature and quenched with water. Theaqueous layer was extracted with ethyl acetate and the combined organiclayers washed with brine, dried over anhydrous sodium sulfate, filtered,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (0%-30% ethyl acetate in petroleumether) to afford2-bromo-2,2-difluoro-N-(2′,3′,4′,6,6′-pentafluoro-4-hydroxy-5′-(2-hydroxyethyl)-[1,1′-biphenyl]-3-yl)acetamide(Compound 1081, 110 mg, 16% yield) as a yellow oil. MS (ESI) calculatedfor (C₁₆H₉BrF₇NO₃) [M−1]⁻ 474.1; found 474.1.

As shown in Step 5 of Scheme 39, To a stirred solution of2-bromo-2,2-difluoro-N-[2′,3′,4′,6,6′-pentafluoro-4-hydroxy-5′-(2-hydroxyethyl)-[1,1′-biphenyl]-3-yl]acetamide(110 mg, 0.23 mmol) in DMF (1 mL) was added and K₂CO₃ (64 mg, 0.46 mmol)at 25° C. under a nitrogen atmosphere. The resulting mixture was stirredat 50° C. for 2 hours under a nitrogen atmosphere, followed bypurification by reversed-phase flash chromatography (0-66% ACN in water)to afford2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-(2-hydroxyethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 65, 70.0 mg, 77% yield) as a yellow solid: MS (ESI) calculatedfor (C₁₆H₈F₇NO₃) [M−1]⁻ 394.0, found 393.9; ¹H-NMR (400 MHz, DMSO-d₆) δ7.02-6.99 (m, 1H), 6.76-6.75 (m, 1H), 4.98-4.84 (m, 1H), 3.61-3.58 (t,J=6.4 Hz, 2H), 2.84 (t, J=6.8 Hz, 2H); ¹⁹F-NMR (377 MHz, DMSO-d6) δ−72.13, −120.85, −125.77, −137.97, −138.05, −166.14.

As shown in Step 6 of Scheme 39, to a stirred solution of2,2,7-trifluoro-6-(2,3,4,6-tetrafluoro-5-(2-hydroxyethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(30 mg, 0.07 mmol) and K₂CO₃ (16 mg, 0.11 mmol) in DMF (1 mL) was added3-bromoprop-1-yne (11 mg, 0.09 mmol) at 25° C. under a nitrogenatmosphere. The resulting mixture was stirred at 25° C. for 2 hoursunder a nitrogen atmosphere, applied to a C₁₈ column, and purified byreversed-phase flash chromatography (0%-70% ACN in water) to afford2,2,7-trifluoro-4-(prop-2-yn-1-yl)-6-(2,3,4,6-tetrafluoro-5-(2-hydroxyethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one(Compound 66, 7 mg, 20% yield) as a white solid: ¹H-NMR (400 MHz,DMSO-d₆) δ 7.77-7.67 (m, 2H), 4.98-4.84 (m, 3H), 3.62 (t, J=6.4 Hz, 2H),3.48-3.40 (m, 1H), 2.87 (t, J=6.8 Hz, 2H); ¹⁹F-NMR (377 MHz, DMSO-d₆) δ−75.02, −115.61, −120.43, −135.10, −137.54, −165.54.

BIOLOGICAL EXAMPLES Example B1. Testing the Herbicidal Activity ofCompounds of the Invention

Protoporphyrinogen oxidase (PPO) inhibition was monitored by the changein fluorescence during the conversion of protoporphyrinogen IX (PPGIX)to protoporphyrin IX (PPIX) (Excitation=550 nm, Emission=625 nm) by PPO.

Cloning of pET28b_PPO_CHis

The coding sequence of AmPPO was optimized for E. coli expression andassembled from synthetic oligonucleotides. Synthetic fragments wereintroduced into a pET28b vector (Novagen) using restriction-less “HotFusion” cloning process (Fu C., et al., ‘Hot Fusion: An Efficient Methodto Clone Multiple DNA Fragments as Well as Inverted Repeats withoutLigase,’ PLoS One (2014) Vol. 9(12), page el 15318). The resulting DNAwas sequence-verified. Construct encoding mutant version (AG210-AmPPO)of the enzyme was produced via PCR-based mutagenesis using Q5mutagenesis kit (NEB).

Amaranthus tuberculatum Protoporphyrinogen Oxidase (AmPPO) Expression

Lysogeny broth (LB media, 10 mL) supplemented with 100 μg/mL kanamyciwas inoculated with a single colony of BL21(DE3) competent E. colitransformed with pET28b_PPO_CHis. [Is pET28b_PPO_CHis. The culture wasgrown at 37° C. with shaking at 230 rpm overnight. This culture was thenused to inoculate 1 L of autoinduction media (AIM) prepared by themethod of Fox, B. G., & Blommel, P. G. (2009), Autoinduction of proteinexpression, ‘Current Protocols in Protein Science,’ Chapter 5,Unit-5.23. The resulting culture was grown at 37° C. with shaking at 230rpm for 4 to 6 hours and an additional 40 to 48 hours at 18° C. Theculture was collected and centrifuged. The resulting AmPPOenzyme-containing cell pellets were frozen and stored at −80° C. forfuture use.

Mutant AmPPO ΔG210 PPO Expression

The same procedure used to produce AmPPO was used to produce mutantΔG210-AmPPO (a PPO mutant in which the glycine at position 210 isabsent), except E. coli used was transformed with pET28b_ΔG210 PPO_CHis.

AmPPO and Mutant ΔG210-AmPPO Purifications

A detergent solution was prepared by mixing together the following: 175mL of B-PER Thermo Scientific); 75 mL of Y-PER (Thermo Scientific); 15mL of 1M TRIS buffer, pH 9.0, 15 mL of 5M NaCl; 50 mL of glycerol; 2.5mL of Triton-X100; and 1 mg of Flavin Adenine Dinucleotide (FAD). Aportion of this solution (about 80 mL-100 mL) is set aside andsupplemented with imidazole to a final concentration of 10 mM and a pHof pH 8.0. The remainder of detergent solution was supplemented with HenEgg White Lysozyme (Gold Bio, 1 mg/mL) and Serratia endonuclease(produced in house) and added to about 45 g of frozen enzyme-containingcell pellets, which were allowed to thaw in the lysis solution withvigorous stirring for 30 minutes at room temperature, then brieflysonicated (30 seconds on 50% power using a VWR brand sonic disruptor).Incubation was continued with stirring for additional 15-30 minutes at4° C. The lysate was clarified for 35 minutes by centrifugation at14,000 RPM. The resulting clarified lysate was incubated for 1 hour at4° C. with gentle stirring with His-SELECT® resin (Sigma, 20 mL of 50%slurry in 20% ethanol, washed 2× with 30 mM TRIS pH 8.1, 10% glycerol,220 mM NaCl). The resin slurry was transferred to a disposable plasticcolumn and washed with 10 mM Imidazole, 250 mM NaCl, 30 mM TRIS pH 8.5,10% glycerol until the bound protein was deemed sufficiently washed awayfrom lysate components (about 6-8 column volumes). The resin was thenwashed thoroughly (about 3 column volumes) with the previously set-asidedetergent I-10 final buffer, followed by elution with the same buffersupplemented with 250 mM imidazole, pH 8.1. Enzyme-containing fractionswere collected and pooled based on SDS-PAGE analysis. Pooled fractionswere diluted with pure glycerol to final concentration of 50% and theAmPPO enzyme or mutant ΔG210-AmPPO was stored at −20° C. in liquid form.

PPO In Vitro Assay

Protoporphyrinogen IX (PPGIX) is prepared by reduction of protoporphyrinIX (PPIX) with a sodium amalgam as described by Jacobs and Jacobs,Enyzme 28: 206 (1982). Once prepared, the PPGIX solution is kept in thedark and all subsequent manipulations of it are performed in the dark.

The Base Buffer for the assay was 50 mM TRIS pH 8.5, 160 mM NaCl, 2 mMDTT, 0.01% Triton X-100. An antifoam solution was prepared by two serial1 to 10 dilutions of Antifoam B Emulsion (SigmaAldrich) with Milli-Qwater. Buffer A was freshly prepared by diluting AmPPO or mutantΔG210-AmPPO in Base Buffer to 3-8 ug/ml concentration of enzyme. BufferB was prepared by adding 2 ml of reduced 2 mM PPIX to 60 ml of BaseBuffer and adjusting the pH back to 8.5 using glacial acetic acid.Finally, antifoam B (Sigma) was added to 0.01% final concentration.Buffer B is unstable, must be protected from light, and should be usedwithin the next 3 hours.

A 384 well, clear bottom plate was used for the assay (black plate ispreferred for the fluorescent assay). Each test compound dissolved inDMSO to a concentration of 30 mM. The test compounds, tested intriplicate, butafenacil control, and a DMSO control were dispensed as1.2 μL drops into a well of the plate. The wells were diluted with 60 μLof Buffer A and serially diluted 1 volume to 3 volumes over 7 dilutionsby removing 20 μL from the first well, mixing well with 40 μL if BufferA in a second well, removing 20 μL from the second well, and continuingthe dilutions in this manner until there were 8 test wells. To initiatethe reaction, 40 μL of Buffer B was added to each well and the wellsgently mixed at least 2 times. The plate was centrifuged at 2000 rpm for1 minute and the absorbance or fluorescence were read at ambienttemperature using a plate reader. IC₅₀'s were calculated using anonlinear regression Sigmoidal dose-response model (GraphPad Prism,variable slope) with curve bottoms constrained to zero and curve topsconstrained to plate-specific V_(average).

Each of Compounds 1 to 38 and 40 to 52 had an IC₅₀ of less than 100 nM.

Example B2. Testing the Post-Emergence Herbicidal Activity of Compoundsof the Invention

Selected compounds of the invention were screened at 100 ppmconcentration against Amaranthus retroflexus (AMARE), Setaria italica(SETIT), and Kochia/Bassia scoparia (KCHSC).

Accordingly, PPO susceptible weed seeds were sown in 5″×5″ pots byquadrant containing Miracle-Gro potting mix (Scotts Miracle-Gro Company,Marysville, OH, USA) and grown in a Conviron growth chamber withappropriate growth conditions (temperature of 26/22° C. with photoperiod16/8 h light day/night and light intensity of 300 μmol m⁻² s⁻¹supplemented by LED lamps). Relative humidity in the growth chamber wasmaintained at around 65%. Plants were grown until 2-4 leaf stage andthinned to 5-8 plants per quadrant per species.

Compounds were formulated in 25% Acetone, 1% Crop oil concentrate(COC-Agridex), 0.1% Tween-20, and 2.5% Ammonium sulphate (AMS). Threereplicate pots were treated with each compound. Treatment consisting ofthe above formulation excluding active compound was applied as atreatment control (TC). Plants were treated with the test compoundsolution in a laboratory spray chamber fitted with 8003 flat fan nozzlescalibrated to deliver 187-200 L ha⁻¹ at 269 kPa. Plants were placed backin the growth chamber and evaluated for % visual injury compared to TC 7days after treatment (DAT). The data presented in Table 3 in which Arepresents a percentage control, where 100% control indicates completeinhibition of weed growth.

Representative compounds 2, 37, and 52 showed excellent herbicidalactivity against weed species at a concentration of 100 parts permillion (PPM), as shown in Table 3.

TABLE 3 Post-emergence herbicidal activity of selected compounds of theinvention 7 days after the compound application Post-emergence % control(100 PPM) Cmpd. No. AMARE SETIT KCHSC 2 98 58 75 37 100 58 92 52 100 7293

Example B3. Testing Leaf Penetration and Translocation with and withoutCrop Oil Concentrate Adjuvant (COC)

Selected compounds of the invention, along with compounds 920-4 and920-6 from Japanese Patent Application No. 06321920, were tested forleaf penetration, translocation, and herbicidal activity in a grass weedspecies when applied with or without an adjuvant to increase thecompound cuticle penetration.

Four to five PPO susceptible Setarialtalica (Foxtail millet) seed (ErnstConservation Seeds, Meadville, PA) were sown in each of the 1.5×1.5-inch6 cell plug inserts containing Miracle-Gro™ potting mix (ScottsMiracle-Gro Company, Marysville, OH, USA) and grown in a Conviron growthchamber with appropriate growth conditions (temperature of 26/22° C.with photoperiod 16/8 h light day/night and light intensity of 300 μmolm⁻² s⁻¹ supplemented by LED lamps). Relative humidity in the growthchamber was maintained at around 65%. Plants were grown until 1-2 leafstage (one expanded leaf and one emerging leaf) and thinned to singleplant per cell.

Test compounds were formulated to a final concentration of 1.5 mM in 25%Acetone, 0.1% Tween-20 and 2.5% Ammonium sulphate (AMS) with or withoutthe addition of 1% v/v Crop oil concentrate (COC, Agridex). A total of 6μL was applied as 3×2 μL droplets on the adaxial surface of an emergedSetaria Italica leaf for each of the two compound solutions (with andwithout COC). Six replicate plants were treated with each compound.Treatment consisting of the above formulation excluding active compoundwas applied as a treatment control (TC). Plants were placed back in thegrowth chamber and, seven days after treatment, were evaluated foroverall % visual injury compared to TC. Plants were also evaluated forrapid necrosis representative of PPO inhibition at the site of,acropetal to, and basipetal to the droplet application site to estimatethe general, xylem, and phloem compound mobility, respectively. Ingeneral, compounds with necrosis only at the site of action wereconsidered to be poorly mobile whereas necrosis in the emerging leafindicates symplastic phloem movement and necrosis from leaf base to tiponly on the applied leaf indicates apoplastic xylem movement.

The data are presented in Table 4 are relative to the TC treatment forwhich the plant and leaf injury percent is consider 0%. “A” represents apercentage leaf or plant injury between 80 and 100%; “B” represents apercentage leaf or plant injury of 20-80%; “C” represents a percentagecontrol below 20%.

As seen in Table 4, Compound Nos. 2, 37, and 52 of the inventionsurprisingly showed significant improved leaf translocation compared tocompounds 920-4 and 920-6.

TABLE 4 Xylem, and phloem mobility for compounds tested. Compound Xylemmobility Phloem mobility No. COC No-COC COC No-COC  2 A A A A 37 A A A A52 A A A A 920-4 A C A C 920-6 A C A C

Compounds 920-4 and 920-6 were also assessed for herbicidal activity asdescribed above in Example 34 and compared with compounds of theinvention as shown in Table 5. An unexpected improvement in herbicidalactivity for the compounds of the invention was observed.

TABLE 5 Herbicidal activity of Compounds 920-4 and 920-6 from JapanesePatent Application No. 06321920 compared to Compounds 2, 37, and 52Cmpd. Post-emergence % control (100 PPM) No. AMARE SETIT KCHSC 920-4 8938 52 920-6 85 18 21  2 98 58 75 37 100 58 92 52 100 72 93

Example B4. Control of PPO-Resistant Weeds Having a dG210 Mutation

A field experiment was conducted to evaluate the efficacy of Compound 2controlling a PPO dG210 mutant Tall Waterhemp (Amaranthus tuberculatus)population. The field location was selected because of historicaldocumentation of several commercial PPO herbicides failing to controlthis weed population. The field was prepared by a standard conventionaltill practice and different herbicide treatments were applied with abackpack carbon dioxide pressurized sprayer at 190 L/ha volume. Theapplications were made to soybean at pre-emergence stage (1 day afterplanting) in 10 meters long by 3 meters wide plots arranged in arandomized complete block layout replicated four times. Herbicides weresurface applied to the vegetation free soil.

Herbicide treatments included Compound 2 formulated as 10% emulsifiedconcentrate, plus the following commercially available herbicides:Flumioxazin 51, a 51% wettable granule formulation of Flumioxazin(RedEagle International LLC); Zidua SC, a 41% suspension concentrateformulation of Pyroxasulfone (BASF Corporation); and Spartan, a 40% dryflowable formulation of Sulfentrazone (FMC Corporation).

Different weed species emergence and development were evaluated fourweeks after the herbicide application and quantified as percent ofgrowth control relative to the untreated control treatment, where totalabsence of control was equal to 0% and complete control was equal to100%. Table 6 shows the degree of control for the different herbicidetreatments and the significant improved biological activity of Compound2 relative to Flumioxazin, Sulfentrazone, and Pyroxasulfone. The data inthe table indicate that Compound 2 was more effective at resistant weedcontrol than the other commercially available herbicides investigated inthe experiment. Also see FIGS. 2A and 2B.

TABLE 6 Rate Weed growth control Compound (gai/ha) (%) Untreated control— 0 Compound 2 30 65 Compound 2 60 97 Compound 2 90 100 Flumioxazin 7043 Sulfentrazone 140 81 Pyroxasulfone 280 64

Further embodiments of the present invention are evident from theclaims, the description, and the examples. It is to be understood thatthe features mentioned above and still to be illustrated below of thesubject matter of the invention can be applied not only in thecombination given in each particular case but also in othercombinations, without leaving the scope of the invention.

What is claimed is:
 1. A compound of formula I:

or a salt thereof, wherein: R¹ is H or C₁₋₄alkyl optionally substitutedwith R^(1a), phenyl, or benzyl, wherein each of said alkyl, phenyl orbenzyl is optionally substituted with up to 3 F atoms, an OH group, oran OC₁₋₄alkyl group; R^(1a) is

each R^(1b) is, independently, H, C₁₋₄alkyl, or cyclopropyl; each of R²and R³ is, independently, H, Cl, F, CH₃, or R² and R³ together with theintervening carbon is cyclopropyl; R⁴ is H, Cl, or F; R⁵ is H or F; eachof R⁶ and R⁷ is, independently, F, H, C₁₋₂alkyl optionally substitutedwith OH, alkenyl, OH, OC₁₋₂alkyl, O-cyclopropyl, OCH₂CCH, NHCH₂Ph,N(R^(x))₂, or SCH₃; R⁸ is H or F; each R^(x) is, independently, H, CH₃,or C(O)CH₃; and wherein Ring A contains at least 4 F atom substituents.2. The compound according to claim 1 having formula II:

or a salt thereof.
 3. The compound according to claim 1 having formulaIII:

or a salt thereof.
 4. The compound according to claim 1 having formulaIV:

or a salt thereof.
 5. The compound according to claim 1, or a saltthereof, wherein each of R², R³, and R⁴ is F.
 6. The compound accordingto claim 1, or a salt thereof, wherein each of R² and R³ is H and R⁴ isF.
 7. The compound according to claim 1, or a salt thereof, wherein eachof R², R³, and R⁴ is F, and R¹ is CH₂CCH.
 8. A compound selected fromthe compounds listed in Table 1, or a salt thereof.
 9. (canceled) 10.(canceled)
 11. The compound of claim 8, or a salt thereof, wherein thecompound is:

or a salt thereof.
 12. An agricultural composition, comprising: acompound of claim 1, or a salt thereof, and at least one additionalcomponent that serves as a carrier.
 13. The composition of claim 12,wherein at least one additional component is a surfactant or a diluent.14. The composition of claim 12, wherein the composition is anherbicidal composition.
 15. A method of controlling undesiredvegetation, comprising contacting the undesired vegetation or itsenvironment with an herbicidally effective amount of compound of claim1, or a salt thereof.
 16. The method of claim 15, wherein the undesiredvegetation comprises weeds.
 17. The method of claim 15, wherein theundesired vegetation comprises protoporphyrinogen IX oxidase (PPO)inhibitor-resistant weeds.
 18. The method of claim 17, wherein the PPOinhibitor-resistant weeds have a dG210 mutation.
 19. The method of claim15, wherein the compound or composition is applied at a rate of 1 to 100g per 10,000 m².
 20. The method of claim 15, wherein contacting theundesired vegetation or its environment with the compound or compositionleads to postemergence control and/or preemergence control of theundesired vegetation.
 21. The method of claim 15, wherein the undesiredvegetation is at least 60% controlled.
 22. The method of claim 15,wherein the undesired vegetation is controlled in a field of corn,soybean, wheat and/or cotton.
 23. A method of preparing a compound offormula (I), or a salt thereof, as recited in claim 1, the methodcomprising: i) deprotecting, a compound of formula (c), or a saltthereof, to yield a compound of formula (d) or a salt thereof,

ii) reducing a compound of formula (d) or a salt thereof, to yield acompound of formula (e) or a salt thereof,

iii) reacting a compound of formula (e), or a salt thereof, with acompound of formula (f), or a salt thereof, to yield a compound offormula (g), or a salt thereof,

iv) cyclizing a compound of formula (g), or a salt thereof to yield acompound of formula (h) or a salt thereof,

and v) reacting a compound of formula (h). or a salt thereof with acompound of formula (i), or a salt thereof, to yield a compound offormula (I), or a salt thereof,

wherein Y is X or B(OH)₂; X is Br or I; and R¹-R⁸ and ring A are asdefined for formula (I).
 24. A method of preparing, a compound offormula (I), or a salt thereof, as recited in claim 1, the methodcomprising reactingg a compound of formula (p), or salt thereof with acompound of formula (q), or a salt thereof, to form a compound offormula (I), or a salt thereof,

wherein: R is H or phenyl; X is Br or I; and R¹-R⁸ and ring A are asdefined for formula (I).
 25. A method of preparing a compound of formula(I), or a salt thereof, as recited in claim 1, the method comprisingreacting a compound of formula (n), or a salt thereof, with a compoundof formula (o), or a salt thereof, to form a compound of formula (I), ora salt thereof,

wherein: R is H or phenyl; X is Br or I; R¹-R⁸ and ring A are as definedfor formula (I).
 26. A compound of formula (c), (di) (e), (g), (h) or(v):

or a salt thereof, wherein: R is H₁ or phenyl; X is Br or 1; and each ofR² and R³ is, independently, W, Cl, F, CH₃, or R² and R³ together withdie intervening carbon is cyclopropyl; R⁴ is H, Cl, or F; R⁵ is H or F;each of R⁶ and R⁷ is, independently, F, H, C₁₋₂alkyl optionallysubstituted with OH, alkenyl, OH, OC₁₋₂alkyl, O-cyclopropyl, OCH₂CCH,NHCH₂Ph, N(R^(x))₂, or SCH₃; R⁸ is H or F; each R^(x) is, independently,H, CH₃, or C(O)CH₃; and wherein Ring A contains at least 4 F atomsubstituents.